New substituted indolinones, preparation thereof and their use as pharmaceutical compositions

ABSTRACT

Indolinones of general formula I  
                 
 
     which are inhibitors of cell proliferation, particularly of tumour cells, and inhibitors of protein kinases.

RELATED APPLICATIONS

[0001] This is a division of Ser. No. 10/002,939 filed Nov. 1, 2001.Benefit of U.S. Provisional Application Serial No. 60/251,055, filed onDec. 1, 2000 is hereby claimed.

DESCRIPTION OF THE INVENTION

[0002] The present invention relates to new substituted indolinones ofgeneral formula

[0003] the isomers, the salts thereof, particularly the physiologicallyacceptable salts thereof which have valuable properties.

[0004] The above compounds of general formula I wherein R₁ is a hydrogenatom or a prodrug group have valuable pharmacological properties,particularly an inhibiting effect on the proliferation of cultivatedhuman tumour cells, but also on the proliferation of other cells,particularly endothelial cells, e.g. in angiogenesis, on variouskinases, particularly on receptor tyrosine kinases (such as, forexample, VEGFR2, EGFR, IGF1R), non-receptor tyrosine kinases (such ase.g. c-src), and serine/threonine kinases (such as e.g. cyclin-dependentkinases), and the other compounds of the above general formula I whereinR₁ does not denote a hydrogen atom or a prodrug group, are valuableintermediate products for the preparation of the compounds mentionedabove.

[0005] The present invention thus relates to the above compounds ofgeneral formula I, wherein

[0006] X denotes an oxygen or sulphur atom,

[0007] R₁ denotes a hydrogen atom, a C₁₋₄-alkoxycarbonyl orC₂₋₄-alkanoyl group,

[0008] R₂ denotes a C₁₋₆-alkyl group optionally substituted by one ormore halogen atoms or a phenyl group or a C₂₋₆-alkenyl group optionallysubstituted by a phenyl group, wherein the phenyl moiety may besubstituted in each case by a fluorine, chlorine, bromine or iodineatom, by a C₁₋₃-alkyl or C₁₋₃-alkoxy group,

[0009] a phenyl group which may be mono- or disubstituted by fluorine,chlorine, bromine or iodine atoms, by C₁₋₃-alkyl or C₁₋₃-alkoxy groups,wherein the substituents may be identical or different,

[0010] a phenyl group substituted by a trifluoromethyl, carboxy,C₁₋₃-alkoxycarbonyl, aminocarbonyl, cyano, aminomethyl, nitro or aminogroup,

[0011] a C₄₋₆-alkyl, C₃₋₇-cycloalkyl, trimethylphenyl or naphthyl group,

[0012] a 5-membered heteroaromatic group optionally substituted by aC₁₋₃-alkyl group, which contains, in the heteroaromatic moiety,

[0013] an imino group optionally substituted by a C₁₋₃-alkyl group, anoxygen or sulphur atom,

[0014] an imino group optionally substituted by a C₁₋₃-alkyl group andan oxygen, sulphur or nitrogen atom,

[0015] an imino group optionally substituted by a C₁₋₃-alkyl group andtwo nitrogen atoms, or an oxygen or sulphur atom and two nitrogen atoms,and to which a phenyl ring may be fused via two adjacent carbon atoms,

[0016] or denotes a 6-membered heteroaromatic group optionallysubstituted by a C₁₋₃-alkyl group, which contains one or two heteroatomsin the heteroaromatic moiety and to which a phenyl ring may be fused viatwo adjacent carbon atoms,

[0017] R₃ denotes a hydrogen atom or a C₁₋₆-alkyl group,

[0018] a phenyl group optionally substituted by a fluorine, chlorine orbromine atom, by a C₁₋₃-alkyl, hydroxy, C₁₋₃-alkoxy,C₁₋₃-alkylsulphenyl, C₁₋₃-alkylsulphinyl, C₁₋₃-alkylsulphonyl,phenylsulphenyl, phenylsulphinyl, phenylsulphonyl, nitro, amino,C₁₋₃-alkylamino, di-(C₁₋₃-alkyl)-amino, C₂₋₅-alkanoylamino orN—(C₁₋₃-alkylamino)-C₂₋₅-alkanoylamino group,

[0019] R4 denotes a phenyl or naphthyl group optionally substituted byR₇, which may additionally be substituted by a chlorine or bromine atomor a nitro group, a 5-membered heteroaromatic group which contains animino group, an oxygen or sulphur atom or an imino group, an oxygen orsulphur atom and one or two nitrogen atoms, or

[0020] a 6-membered heteroaromatic group which contains one, two orthree nitrogen atoms, while the abovementioned 5- and 6-memberedheteroaromatic groups may additionally be substituted by a chlorine orbromine atom or by a methyl group or wherein a phenyl ring may be fusedto the abovementioned 5- and 6-membered heteroaromatic groups via 2adjacent carbon atoms, or

[0021] R₅ and R₆ in each case independently of one another denotehydrogen atoms or C₁₋₃-alkyl groups, and

[0022] R₇ denotes a fluorine, chlorine, bromine or iodine atom or acyano group, a methoxy group or a C₂₋₃-alkoxy group, which may besubstituted in the 2 or 3 position by an amino, C₁₋₃-alkylamino,di-(C₁₋₃-alkyl)-amino or 5- to 7-membered cycloalkyleneimino group,while in each case an alkyl moiety in the above-mentioned alkylamino anddialkylamino groups may additionally be substituted by a phenyl group,

[0023] a trifluoromethyl, nitro, amino, C₁₋₃-alkylamino,di-(C₁₋₃-alkyl)-amino,

[0024] C₂₋₅-alkanoylamino, N—(C₁₋₃-alkyl)-C₂₋₅-alkanoylamino,C₁₋₅-alkylsulphonylamino, N—(C₁₋₃-alkyl)-C₁₋₅-alkylsulphonylamino,phenylsulphonylamino, N—(C₁₋₃-alkyl)-phenylsulphonylamino,aminosulphonyl, C₁₋₃-alkylaminosulphonyl ordi-(C₁₋₃-alkyl)-aminosulphonyl group, while in each case an alkyl moietyin the above-mentioned alkylamino and dialkylamino groups mayadditionally be substituted by a carboxy, C₁₋₃-alkoxycarbonyl,aminocarbonyl, C₁₋₃-alkylaminocarbonyl, di-(C₁₋₃-alkyl)-aminocarbonyl,2-dimethylaminoethylaminocarbonyl orN-methyl-(2-dimethylaminoethyl)-aminocarbonyl group and in each case thealkyl moiety of the abovementioned alkanoylamino or alkysulphonylaminogroups may additionally be substituted by a phenyl, amino,C₁₋₃-alkylamino, di-(C₁₋₃-alkyl)-amino or a 4- to 7-memberedcycloalkyleneimino group,

[0025] a C₂₋₄-alkylamino group which is terminally substituted in the2,3- or 4 position by an amino, C₁₋₃-alkylamino, di-(C₁₋₃-alkyl)-amino,benzylamino, N—(C₁₋₃-alkyl)-benzylamino, C₂₋₅-alkanoylamino orN—(C₁₋₃-alkyl)-C₂₋₅-alkanoylamino group and wherein additionally theamino-hydrogen atom may be replaced by a C₂₋₅-alkanoyl, benzoyl,C₁₋₅-alkylsulphonyl- or phenylsulphonyl group, while the last-mentionedC₂₋₅-alkanoyl or C₁₋₅-alkylsulphonyl groups in the alkyl moiety may besubstituted by a phenyl group,

[0026] a carbonyl group which is substituted by a hydroxy, C₁₋₃-alkoxy,amino, C₁₋₃-alkylamino, N—(C₁₋₅-alkyl)-C₁₋₃-alkylamino orC₅₋₇-cycloalkyleneimino group;

[0027] a C₁₋₃-alkyl group which may be substituted by an amino,C₁₋₅-alkylamino,

[0028] C₅₋₇-cycloalkylamino or phenyl-C₁₋₃-alkylamino group which mayadditionally be substituted at the amino nitrogen atom in each case by aC₁₋₄-alkyl, Cs-7-cycloalkyl or C₂₋₄-alkenyl- or C₁₋₄-alkyl group, while

[0029] the abovementioned C₁₋₄-alkyl substituent in each case mayadditionally be mono-, di- or trisubstituted by a cyano, carboxy,C₁₋₃-alkoxycarbonyl, C₂₋₄-alkanoyl, pyridyl, imidazolyl,benzo[1,3]dioxol or phenyl group, while the phenyl group may besubstituted by fluorine, chlorine or bromine atoms, by methyl, methoxy,trifluoromethyl, cyano or nitro groups and the substituents may beidentical or different, or in the 2, 3 or 4 position by a hydroxy group,

[0030] a C₁₋₃-alkyl group which is substituted by a hydroxy, carboxy,morpholino, thiomorpholino, 1-oxo-thiomorpholino,1,1-dioxo-thiomorpholino, piperazino, N—(C₁₋₃-alkyl)-piperazino orN-benzyl-piperazino group, by a 5- to 7-membered cycloalkenyleneiminogroup or by a 4- to 7-membered cycloalkyleneimino group, while theabovementioned 5- to 7-membered cycloalkyleneimino groups may besubstituted by one or two C₁₋₃-alkyl groups, which may in turn beterminally substituted by a hydroxy, amino or C₂₋₄-alkanoylamino group,or by a C₅₋₇-cycloalkyl or phenyl group and by a hydroxy group and inthe abovementioned cycloalkyleneimino groups a methylene group adjacentto the nitrogen atom may be replaced by a carbonyl group,

[0031] a C₁₋₃-alkyl group which is substituted by a 5- to 7-memberedcycloalkyleneimino group, while a phenyl group optionally mono- ordisubstituted by fluorine, chlorine or bromine atoms or by methyl ormethoxy groups, wherein the substituents may be identical or different,or an oxazolo, imidazolo, thiazolo, pyridino, pyrazino or pyrimidinogroup optionally substituted by a fluorine, chlorine, bromine or iodineatom, by a methyl, methoxy or amino group is fused to the abovementioned5- to 7-membered cycloalkyleneimino groups via 2 adjacent carbon atoms,while the above-mentioned monosubstituted phenyl groups may additionallybe substituted by a fluorine, chlorine or bromine atom, by a methyl,methoxy or nitro group, or

[0032] denotes an imidazolyl or 1H-C₁₋₃-alkylimidazolyl group.

[0033] If R₁ denotes a hydrogen atom, the present invention also relatesto the tautomeric compounds of formula I′

[0034] The invention also relates to compounds of formula I, wherein R₁denotes a cleavable prodrug group.

[0035] The invention further relates to pharmaceutical compositionscontaining the pharmacologically active compound, their use andprocesses for preparing them.

[0036] Preferred compounds of formula I are those wherein thesulphonylamino group of formula R₂—SO₂NR₆— is linked to the 5-positionof the indolinone group.

[0037] Preferred compounds of formula I are those wherein

[0038] R₇ denotes a C₁₋₃-alkyl group which is substituted by a hydroxy,carboxy, morpholino, thiomorpholino, 1-oxo-thiomorpholino,1,1-dioxo-thiomorpholino, piperazino, N—(C₁₋₃-alkyl)-piperazino orN-benzyl-piperazino group, by a 5- to 7-membered cycloalkenyleneiminogroup or by a 4- to 7-membered cycloalkyleneimino group, while theabovementioned 5- to 7-membered cycloalkyleneimino groups may besubstituted by one or two C₁₋₃-alkyl groups, which may in turn beterminally substituted by an amino or C₂₋₄-alkanoylamino group, or by aC₅₋₇-cycloalkyl or phenyl group and by a hydroxy group and in theabovementioned cycloalkyleneimino groups a methylene group adjacent tothe nitrogen atom may be replaced by a carbonyl group.

[0039] Also preferred are compounds of formula I wherein

[0040] R₃ denotes a phenyl group optionally substituted by a fluorine,chlorine or bromine atom, by a C₁₋₃-alkyl, hydroxy, C₁₋₃-alkoxy,C₁₋₃-alkylsulphenyl, C₁₋₃-alkylsulphinyl, C₁₋₃-alkylsulphonyl,phenylsulphenyl, phenylsulphinyl, phenylsulphonyl, nitro, amino,C₁₋₃-alkylamino, di-(C₁₋₃-alkyl)-amino, C₂₋₅-alkanoylamino orN—(C₁₋₃-alkylamino)-C₂₋₅-alkanoylamino group, more particularly a phenylgroup optionally substituted by an fluorine, chlorine, bromine or iodineatom, by a C₁₋₃-alkyl, C₁₋₃-alkoxy, nitro or amino group.

[0041] In another preferred embodiment R₂ denotes a C₁₋₄-alkyl groupoptionally substituted by one or more halogen atoms or a phenyl group, aC₃₋₅-cycloalkyl group or a C₂₋₄-alkenyl group optionally substituted bya phenyl group, wherein the phenyl moiety in each case may besubstituted by a fluorine, chlorine, bromine or iodine atom or by aC₁₋₃-alkyl or C₁₋₃-alkoxy.

[0042] Moreover, the carboxy, amino or imino groups present in acompound of the above general formula I may be substituted by groupswhich can be cleaved in vivo.

[0043] In addition to the alkoxycarbonyl and alkanoyl groups alreadymentioned hereinbefore, groups which can be cleaved in vivo may also beincluded, such as an acyl group such as the benzoyl, pyridinoyl,pentanoyl or hexanoyl group, an allyloxycarbonyl group, aC₁₋₁₆-alkoxycarbonyl group such as the tert-butyloxycarbonyl,pentyloxycarbonyl, hexyloxycarbonyl, octyloxycarbonyl, nonyloxycarbonyl,decyloxycarbonyl, undecyloxycarbonyl, dodecyloxycarbonyl orhexadecyloxycarbonyl group, a phenyl-C₁₋₆-alkoxycarbonyl group such asthe benzyloxycarbonyl, phenylethoxycarbonyl or phenylpropoxycarbonylgroup, a C₁₋₃-alkylsulphonyl-C₂₋₄-alkoxycarbonyl,C₁₋₃-alkoxy-C₂₋₄-alkoxy-C₂₋₄-alkoxycarbonyl orR_(c)CO—O—(R_(d)CR_(e))—O—CO-group, wherein

[0044] R_(c) denotes a C₁₋₈-alkyl, C₅₋₇-cycloalkyl, phenyl- orphenyl-C₁₋₃-alkyl group, Re denotes a hydrogen atom, a C₁₋₃-alkyl,C₅₋₇-cycloalkyl or phenyl group and Rd denotes a hydrogen atom or aC₁₋₃-alkyl group or a R_(f)CO—O—(R_(g)CR_(h))—O-Rest wherein

[0045] R_(f) denotes a C₁₋₈-alkyl, C₅₋₇-cycloalkyl, phenyl orphenyl-C₁₋₃-alkyl group,

[0046] R_(p) denotes a hydrogen atom, a C₁₋₃-alkyl, C₅₋₇-cycloalkyl orphenyl group and

[0047] R_(h) denotes a hydrogen atom or a C₁₋₃-alkyl group,

[0048] while the abovementioned ester groups may also be used as a groupwhich can be converted in vivo into a carboxy group.

[0049] Preferred compounds of the above general formula I are thosewherein

[0050] X denotes an oxygen atom,

[0051] R₁ denotes a hydrogen atom,

[0052] R₂ denotes a C₁₋₃-alkyl group optionally substituted by one ormore fluorine atoms or a phenyl group or a C₂₋₄-alkenyl group optionallysubstituted by a phenyl group;

[0053] a phenyl group which may be mono- or disubstituted by fluorine,chlorine, bromine or iodine atoms, by C₁₋₃-alkyl or C₁₋₃-alkoxy groups,wherein the substituents may be identical or different,

[0054] a phenyl group substituted by a trifluoromethyl, carboxy,C₁₋₃-alkoxycarbonyl, aminocarbonyl, cyano, aminomethyl, nitro or aminogroup,

[0055] a C₄₋₆-alkyl, C₃₋₇-cycloalkyl, trimethylphenyl or naphthyl group,or

[0056] a pyridinyl, quinolyl, isoquinolyl, oxazolyl, isoxazolyl,imidazolyl or 1-(C₁₋₃-alkyl)-imidazolyl group optionally substituted bya C₁₋₃-alkyl group,

[0057] R₃ denotes a hydrogen atom or a C₁₋₄-alkyl group, or

[0058] a phenyl group optionally substituted by a fluorine, chlorine,bromine or iodine atom, by a C₁₋₃-alkyl, C₁₋₃-alkoxy, nitro or aminogroup,

[0059] R₄ denotes a phenyl group optionally substituted by R₇, which mayadditionally be substituted by a chloro or nitro group,

[0060] R₅ and R₆ in each case denote a hydrogen atom, and

[0061] R₇ denotes a fluorine, chlorine, bromine or iodine atom,

[0062] a methoxy, nitro, cyano, carboxy, C₁₋₃-alkoxycarbonyl,aminocarbonyl, C₁₋₃-alkylaminocarbonyl, di-(C₁₋₃-alkyl)-aminocarbonyl,phenyl-C₁₋₃-alkylaminocarbonyl,N-(phenyl-C₁₋₃-alkyl)-C₁₋₃-alkylaminocarbonyl or 5- to 7-memberedcycloalkyleneiminocarbonyl group,

[0063] a C₁₋₃-alkyl group which is substituted by a carboxy,C₁₋₃-alkoxycarbonyl, aminocarbonyl, C₁₋₃-alkylaminocarbonyl,di-(C₁₋₃-alkyl)-aminocarbonyl, phenyl-C₁₋₃-alkylaminocarbonyl,N-(phenyl-C₁₋₃-alkyl)-C₁₋₃-alkylaminocarbonyl, 5- to 7-memberedcycloalkyleneiminocarbonyl, amino, C₁₋₃-alkylamino,di-(C₁₋₃-alkyl)-amino, phenyl-C₁₋₃-alkylamino,N-(phenyl-C₁₋₃-alkyl)-C₁₋₃-alkylamino or 5- to 7-memberedcycloalkyleneimino group,

[0064] while the abovementioned 5- to 7-membered cycloalkyleneiminogroup may be substituted by one or two C₁₋₃-alkyl groups, which may inturn be terminally substituted by a hydroxy, amino or C₂₋₄-alkanoylaminogroup, and at the same time in the abovementioned 5- to 7-memberedcycloalkyleneimino moieties a methylene group in the 2 position may bereplaced by a carbonyl group or in the abovementioned 6- and 7-memberedcycloalkyleneimino moieties a methylene group in the 4 position may bereplaced by an oxygen atom, by an imino, N—(C₁₋₃-alkyl)-imino,N-(phenyl-C₁₋₃-alkyl)-imino or N—(C₁₋₅-alkoxycarbonyl)-imino group,

[0065] an amino, C₁₋₃-alkylamino, phenyl-C₁₋₃-alkylamino,C₁₋₅-alkanoylamino, phenyl-C₁₋₄-alkanoylamino, C₁₋₅-alkoxycarbonylamino,phenyl-C₁₋₃-alkoxycarbonylamino, C₁₋₅-alkylsulphonylamino,phenyl-C₁₋₃-alkylsulphonylamino- or phenylsulphonylamino group, whereinthe hydrogen atom of the amino group may be replaced by a C₁₋₃-alkylgroup, while the C₁₋₃-alkyl moiety may be substituted by a carboxy,C₁₋₃-alkoxycarbonyl, aminocarbonyl, C₁₋₃-alkylaminocarbonyl,di-(C₁₋₃-alkyl)-aminocarbonyl, phenyl-C₁₋₃-alkylaminocarbonyl,N-(phenyl-C₁₋₃-alkyl)-C₁₋₃-alkylaminocarbonyl,2-dimethylaminoethylaminocarbonyl,N-methyl-(2-dimethylaminoethyl)-aminocarbonyl- orC₄₋₆-cycoalkylenimnocarbonyl group or from position 2 by an amino,C₁₋₃-alkylamino, di-(C₁₋₃-alkyl)-amino, phenyl-C₁₋₃-alkylamino,N-(phenyl-C₁₋₃-alkyl)-C₁₋₃-alkylamino, C₂₋₅-alkanoylamino,N—(C₁₋₃-alkyl)-C₂₋₅-alkanoylamino, C₁₋₅-alkoxycarbonylamino- orN—(C₁₋₅-alkoxycarbonyl)-C₁₋₃-alkylamino group,

[0066] imidazolyl or 1-C₁₋₃-alkylimidazolyl group.

[0067] Particularly preferred compounds of formula I are those wherein

[0068] R₇ denotes a C₁₋₃-alkyl group which is substituted by a carboxy,C₁₋₃-alkoxycarbonyl, aminocarbonyl, C₁₋₃-alkylaminocarbonyl,di-(C₁₋₃-alkyl)-aminocarbonyl, phenyl-C₁₋₃-alkylaminocarbonyl,N-(phenyl-C₁₋₃-alkyl)-C₁₋₃-alkylaminocarbonyl, 5- to 7-memberedcycloalkyleneiminocarbonyl, amino, C₁₋₃-alkylamino,di-(C₁₋₃-alkyl)-amino, phenyl-C₁₋₃-alkylamino,N-(phenyl-C₁₋₃-alkyl)-C₁₋₃-alkylamino- or 5- to 7-memberedcycloalkyleneimino group,

[0069] while the abovementioned 5- to 7-membered cycloalkyleneiminogroup may be substituted by one or two C₁₋₃-alkyl groups, which may inturn be terminally substituted by an amino or C₂₋₄-alkanoylamino group,and at the same time in the abovementioned 5-to 7-memberedcycloalkyleneimino moieties a methylene group may be replaced in the 2position by a carbonyl group or in the abovementioned 6- and 7-memberedcycloalkyleneimino moieties a methylene group in the 4 position may bereplaced by an oxygen atom, by an imino, N—(C₁₋₃-alkyl)-imino,N-(phenyl-C₁₋₃-alkyl)-imino or N—(C₁₋₅-alkoxycarbonyl)-imino group.

[0070] Particularly preferred compounds of general formula I are thosewherein

[0071] X denotes an oxygen atom,

[0072] R₁ denotes a hydrogen atom,

[0073] R₂ denotes a C₁₋₃-alkyl group optionally substituted by a phenylgroup, a C₁₋₃-perfluoroalkyl group or a phenylvinyl group,

[0074] a phenyl group which may be substituted by a fluorine, chlorine,bromine or iodine atom, by a C₁₋₃-alkyl, C₁₋₃-alkoxy, nitro, amino,cyano or aminomethyl group,

[0075] a C₄₋₆-alkyl, C₃₋₇-cycloalkyl, trimethylphenyl or naphthyl group,

[0076] a pyridinyl, quinolyl, isoquinolyl, oxazolyl, isoxazolyl,imidazolyl or 1-(C₁₋₃-alkyl)-imidazolyl group optionally substituted bya C₁₋₃-alkyl group,

[0077] R₃ denotes a phenyl group optionally substituted by a fluorine,chlorine, bromine or iodine atom, by a C₁₋₃-alkyl, C₁₋₃-alkoxy, nitro oramino group,

[0078] R₄ denotes a phenyl group which may be substituted by R₇ andadditionally by a chlorine atom or a nitro group, while

[0079] R₇ denotes a fluorine, chlorine, bromine or iodine atom,

[0080] a methoxy, nitro, cyano, carboxy, methoxycarbonyl, aminocarbonyl,methylaminocarbonyl, dimethylaminocarbonyl, benzylaminocarbonyl,N-benzylmethylaminocarbonyl, pyrrolidinocarbonyl or piperidinocarbonylgroup, a methyl or ethyl group which may be substituted by a carboxy,methoxycarbonyl, aminocarbonyl, methylaminocarbonyl,dimethylaminocarbonyl, benzylaminocarbonyl,N-benzyl-methylaminocarbonyl, pyrrolidinocarbonyl, piperidinocarbonyl,amino, C₁₋₄-alkylamino, di-C₁₋₄-alkylamino, benzylamino,N-benzyl-C₁₋₄-alkylamino, C₂₋₄-alkanoylamino,N—C₁₋₄-alkyl-C₂₋₄-alkanoylamino, tert.butyloxycarbonylamino,N-methyl-tert.butyloxycarbonylamino, pyrrolidino, pyrrolidinomethyl,hydroxypyrrolidinomethyl, hydroxymethylpyrrolidinomethyl, piperidino,4-(3-aminopropyl)-piperidino, 4-(3-acetylaminopropyl)-piperidino,dimethylpiperidino, 2-oxo-piperidino, piperazino, 4-methyl-piperazino,4-benzyl-piperazino, 4-tert.butoxycarbonylpiperazino or morpholinogroup, or

[0081] an amino, methylamino, ethylamino, C₁₋₃-alkanoylamino,phenylacetylamino, tert.butoxycarbonylamino,piperidinomethylcarbonylamino, C₁₋₄-alkylsulphonylamino,phenyl-methylsulphonylamino or phenylsulphonylamino group, wherein thehydrogen atom of the amino group may be replaced by a methyl, ethyl orpropyl group, while the methyl or ethyl moiety in each case may besubstituted by a carboxy, methoxycarbonyl, aminocarbonyl,methylaminocarbonyl, dimethylaminocarbonyl,2-dimethylaminoethylaminocarbonyl orN-methyl-(2-dimethylaminoethyl)-aminocarbonyl group or the ethyl moietymay also be substituted from position 2 by an amino, methylamino,dimethylamino, benzylalkylamino, N-benzyl-methylamino,C₂₋₃-alkanoylamino, N-methyl-C₂₋₃-alkanoylamino,tert.butyloxycarbonylamino or N-methyl-tert.butyloxycarbonylamino group,

[0082] an imidazolyl or 1-methylimidazolyl group,

[0083] R₅ and R₆ in each case denote a hydrogen atom,

[0084] and the isomers and the salts thereof.

[0085] Particularly preferred are compounds of formula I wherein R₄denotes a phenyl group substituted by R₇ in the 3 or 4 position,particularly in the 4 position.

[0086] According to the invention, the new compounds are obtained, forexample, by the following methods known in principle from theliterature:

[0087] a. reacting a compound of general formula

[0088] wherein

[0089] X, R₂, R₃ and R₆ are as hereinbefore defined and

[0090] R₈ has one of the meanings given for R₁ or may denote aprotecting group for the nitrogen atom of the lactam group, while R₈ mayalso represent a bond to a solid phase optionally formed via a spacer,and

[0091] Z₁ denotes a halogen atom, a hydroxy, alkoxy or aralkoxy group,e.g. a chlorine or bromine atom, a methoxy, ethoxy or benzyloxy group,

[0092] with an amine of general formula

[0093] wherein

[0094] R₄ and R₅ are as hereinbefore defined,

[0095] and if necessary subsequently cleaving any protecting group usedfor the nitrogen atom of the lactam group or from a solid phase.

[0096] The protecting group used for the nitrogen atom of the lactamgroup may be, for example, an acetyl, benzoyl, ethoxycarbonyl,tert.butyloxycarbonyl or benzyloxycarbonyl group and

[0097] the solid phase used may be a resin such as a4-(2′,4′-dimethoxyphenylaminomethyl)-phenoxy resin, while the bond mayexpediently be effected via the amino group, or a p-benzyloxybenzylalcohol resin, while the bond may expediently be effected via anintermediate member such as a 2,5-dimethoxy-4-hydroxy-benzyl derivative.

[0098] The reaction is conveniently carried out in a solvent such asdimethylformamide, toluene, acetonitrile, tetrahydrofuran,dimethylsulphoxide, dichloromethane or mixtures thereof, optionally inthe presence of an inert base such as triethylamine,N-ethyl-diisopropylamine or sodium hydrogen carbonate at temperaturesbetween 20 and 175° C., while any protecting group used maysimultaneously be cleaved by transamidation.

[0099] If Z₁ in a compound of general formula II denotes a halogen atom,the reaction is preferably carried out in the presence of an inert baseat temperatures between 20 and 120° C.

[0100] If Z₁ in a compound of general formula II denotes a hydroxy,alkoxy or aralkoxy group, the reaction is preferably carried out attemperatures between 20 and 200° C.

[0101] If any protecting group used subsequently has to be cleaved, thisis conveniently carried out either hydrolytically in an aqueous oralcoholic solvent, e.g. in methanol/water, ethanol/water,isopropanol/water, tetrahydrofuran/water, dioxane/water,dimethylformamide/water, methanol or ethanol in the presence of analkali metal base such as lithium hydroxide, sodium hydroxide orpotassium hydroxide at temperatures between 0 and 100° C., preferably attemperatures between 10 and 50° C.,

[0102] or advantageously by transamidation with an organic base such asammonia, methylamine, butylamine, dimethylamine or piperidine in asolvent such as methanol, ethanol, dimethylformamide and mixturesthereof or in an excess of the amine used at temperatures between 0 and100° C., preferably at temperatures between 10 and 50° C.

[0103] Any solid phase used is preferably cleaved using trifluoroaceticacid and water at temperatures between 0 and 35° C., preferably atambient temperature.

[0104] b. reacting a compound of general formula

[0105] wherein

[0106] R₁ and R₃ to R₆ are as hereinbefore defined, with a compound ofgeneral formula

R₂—SO₂—OH  (V),

[0107] wherein

[0108] R₂ is as hereinbefore defined, or with the reactive derivativesthereof.

[0109] The reaction is preferably carried out in a solvent such asdichloromethane, diethylether, tetrahydrofuran, toluene, dioxane,acetonitrile, dimethylsulphoxide or

[0110] dimethylformamide, optionally with a reactive derivative of acompound of general formula V such as the halide thereof, in thepresence of an inorganic or tertiary organic base, preferably attemperatures between 0° C. and the boiling temperature of the solventused, preferably at temperatures between 50 and 100° C.

[0111] With a corresponding sulphonic acid the reaction is preferablycarried out in the presence of a dehydrating agent, e.g. in the presenceof isobutyl chloroformate, tetraethyl orthocarbonate, trimethylorthoacetate, 2,2-dimethoxypropane, tetramethoxysilane, thionylchloride, trimethylchlorosilane, phosphorus trichloride, phosphoruspentoxide, N,N′-dicyclohexylcarbodiimide,N,N′-dicyclohexylcarbodiimide/N-hydroxysuccinimide,N,N′-dicyclohexylcarbodiimide/1-hydroxy-benztriazole,2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium-tetrafluoroborate,2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium-tetrafluoroborate/1-hydroxy-benzotriazole,N,N′-carbonyldiimidazole or triphenylphosphine/carbon tetrachloride, andoptionally with the addition of a base such as pyridine,4-dimethylaminopyridine, N-methyl-morpholine or triethylamine,expediently at temperatures between 0 and 150° C., preferably attemperatures between 0 and 100° C.

[0112] If according to the invention a compound of general formula I isobtained which contains an alkoxycarbonyl group, this can be convertedby hydrolysis into a corresponding carboxy compound, or

[0113] if a compound of general formula I is obtained which contains anamino or alkylamino group, this may be converted by reductive alkylationinto a corresponding alkylamino or dialkylamino compound, or

[0114] if a compound of general formula I is obtained which contains anamino or alkylamino group, this may be converted by acylation into acorresponding acyl compound, or

[0115] if a compound of general formula I is obtained which contains acarboxy group, this may be converted by esterification or amidation intoa corresponding ester or aminocarbonyl compound, or

[0116] if a compound of general formula I is obtained which contains anitro group, this can be converted by reduction into a correspondingamino compound, or

[0117] if a compound of general formula I is obtained which contains acyano group, this can be converted by reduction into a correspondingaminomethyl compound.

[0118] The subsequent hydrolysis is preferably carried out in an aqueoussolvent, e.g. in water, isopropanol/water, tetrahydrofuran/water ordioxane/water, in the presence of an acid such as trifluoroacetic acid,hydrochloric acid or sulphuric acid or in the presence of an alkalimetal base such as lithium hydroxide, sodium hydroxide or potassiumhydroxide at temperatures between 0 and 100° C., preferably attemperatures between 10 and 50° C.

[0119] The subsequent reductive alkylation is preferably carried out ina suitable solvent such as methanol, methanol/water,methanol/water/ammonia, ethanol, ether, tetrahydrofuran, dioxane ordimethylformamide, optionally with the addition of an acid such ashydrochloric acid in the presence of catalytically activated hydrogen,e.g. hydrogen in the presence of Raney nickel, platinum orpalladium/charcoal, or in the presence of a metal hydride such as sodiumborohydride, sodium cyanoborohydride, lithium borohydride or lithiumaluminium hydride at temperatures between 0 and 100° C., preferably attemperatures between 20 and 80° C.

[0120] The subsequent acylation is preferably carried out in a solventsuch as methylene chloride, diethylether, tetrahydrofuran, toluene,dioxane, acetonitrile, dimethylsulphoxide or dimethylformamide,optionally in the presence of an inorganic or a tertiary organic base,preferably at temperatures between 20° C. and the boiling temperature ofthe solvent used. The acylation with a corresponding acid is preferablycarried out in the presence of a dehydrating agent, e.g. in the presenceof isobutyl chloroformate, tetraethyl orthocarbonate, trimethylorthoacetate, 2,2-dimethoxypropane, tetramethoxysilane, thionylchloride,trimethylchlorosilane, phosphorus trichloride, phosphorus pentoxide,N,N′-dicyclohexylcarbodiimide,N,N′-dicyclohexyl-carbodiimide/N-hydroxysuccinimide,N,N′-dicyclohexylcarbodiimide/1-hydroxy-benztriazole,2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium-tetrafluoroborate,2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium-tetrafluoroborate/1-hydroxy-benzotriazole,N,N′-carbonyldiimidazole or triphenylphosphine/carbon tetrachloride, andoptionally with the addition of a base such as pyridine,4-dimethylamino-pyridine, N-methyl-morpholine or triethylamine,conveniently at temperatures between 0 and 150° C., preferably attemperatures between 0 and 100° C., and the acylation with acorresponding reactive compound such as an anhydride, ester, imidazolideor halide thereof is optionally carried out in the presence of atertiary organic base such as triethylamine, N-ethyl-diisopropylamine orN-methyl-morpholine at temperatures between 0 and 150° C., preferably attemperatures between 50 and 100° C.

[0121] The subsequent esterification or amidation is expediently carriedout by reacting a corresponding reactive carboxylic acid derivative witha corresponding alcohol or amine as described hereinbefore.

[0122] The subsequent reduction of a nitro group is preferably carriedout by hydrogenolysis, e.g. with hydrogen in the presence of a catalystsuch as palladium/charcoal or Raney nickel in a solvent such asmethanol, ethanol, ethyl acetate, dimethylformamide,dimethylformamide/acetone or glacial acetic acid, optionally with theaddition of an acid such as hydrochloric acid or glacial acetic acid attemperatures of between 0 and 50° C., but preferably at ambienttemperature, and at a hydrogen pressure of 1 to 7 bar, but preferably 3to 5 bar.

[0123] The subsequent reduction of a cyano group is preferably carriedout by hydrogenolysis, e.g. with hydrogen in the presence of a catalystsuch as palladium/charcoal or Raney nickel in a solvent such asmethanolic ammonia, ethanolic ammonia, ethyl acetate, dimethylformamide,dimethylformamide/acetone, dichloromethane or glacial acetic acid,optionally with the addition of an acid such as hydrochloric acid orglacial acetic acid at temperatures of between 0 and 50° C., butpreferably at ambient temperature, and at a hydrogen pressure of 1 to 7bar, but preferably 3 to 5 bar.

[0124] In the reactions described hereinbefore, any reactive groupspresent such as carboxy, amino, alkylamino or imino groups may beprotected during the reaction by conventional protecting groups whichare cleaved again after the reaction.

[0125] For example, a protecting group for a carboxyl group may be atrimethylsilyl, methyl, ethyl, tert.butyl, benzyl or tetrahydropyranylgroup and protecting groups for an amino, alkylamino or imino group maybe an acetyl, trifluoroacetyl, benzoyl, ethoxycarbonyl,tert.butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxybenzyl or2,4-dimethoxybenzyl group and additionally, for the amino group, aphthalyl group.

[0126] Any protecting group used is optionally subsequently cleaved forexample by hydrolysis in an aqueous solvent, e.g. in water,isopropanol/water, tetrahydrofuran/water or dioxane/water, in thepresence of an acid such as trifluoroacetic acid, hydrochloric acid orsulphuric acid or in the presence of an alkali metal base such aslithium hydroxide, sodium hydroxide or potassium hydroxide, attemperatures between 0 and 100° C., preferably at temperatures between10 and 50° C.

[0127] However, a benzyl, methoxybenzyl or benzyloxycarbonyl group iscleaved, for example, hydrogenolytically, e.g. with hydrogen in thepresence of a catalyst such as palladium/charcoal in a solvent such asmethanol, ethanol, ethyl acetate, dimethylformamide,dimethylformamide/acetone or glacial acetic acid, optionally with theaddition of an acid such as hydrochloric acid or glacial acetic acid attemperatures between 0 and 50° C., but preferably at ambienttemperature, and at a hydrogen pressure of 1 to 7 bar, but preferably 3to 5 bar.

[0128] A methoxybenzyl group may also be cleaved in the presence of anoxidising agent such as cerium(IV)ammonium nitrate in a solvent such asmethylene chloride, acetonitrile or acetonitrile/water at temperaturesof between 0 and 50° C., but preferably at ambient temperature.

[0129] A 2,4-dimethoxybenzyl group, however, is preferably cleaved intrifluoroacetic acid in the presence of anisol.

[0130] A tert.butyl or tert.butyloxycarbonyl group is preferably cleavedby treating with an acid such as trifluoroacetic acid or hydrochloricacid, optionally using a solvent such as methylene chloride, dioxane,ethyl acetate or ether.

[0131] A phthalyl group is preferably cleaved in the presence ofhydrazine or a primary amine such as methylamine, ethylamine orn-butylamine in a solvent such as methanol, ethanol, isopropanol,toluene/water or dioxane at temperatures between 20 and 50° C.

[0132] Moreover, chiral compounds of general formula I obtained may beresolved into their enantiomers and/or diastereomers.

[0133] Thus, for example, the compounds of general formula I obtainedwhich occur as racemates may be separated by methods known per se (cf.Allinger N. L. and Eliel E. L. in “Topics in Stereochemistry”, Vol. 6,Wiley Interscience, 1971) into their optical antipodes and compounds ofgeneral formula I with at least 2 asymmetric carbon atoms may beresolved into their diastereomers on the basis of theirphysical-chemical differences using methods known per se, e.g. bychromatography and/or fractional crystallisation, and, if thesecompounds are obtained in racemic form, they may subsequently beresolved into the enantiomers as mentioned above.

[0134] The enantiomers are preferably separated by column separation onchiral phases or by recrystallisation from an optically active solventor by reacting with an optically active substance which forms salts orderivatives such as e.g. esters or amides with the racemic compound,particularly acids and the activated derivatives or alcohols thereof,and separating the diastereomeric mixture of salts or derivatives thusobtained, e.g. on the basis of their differences in solubility, whilstthe free antipodes may be released from the pure diastereomeric salts orderivatives by the action of suitable agents. Optically active acids incommon use are e.g. the D- and L-forms of tartaric acid ordibenzoyltartaric acid, di-o-tolyltartaric acid, malic acid, mandelicacid, camphorsulphonic acid, glutamic acid, N-acetylglutamic acid,aspartic acid, N-acetylaspartic acid or quinic acid. An optically activealcohol may be for example (+)- or (−)-menthol and an optically activeacyl group in amides, for example, may be a (+)- or(−)-menthyloxycarbonyl group.

[0135] Furthermore, the compounds of formula I obtained may be convertedinto the salts thereof, particularly for pharmaceutical use into thephysiologically acceptable salts with inorganic or organic acids. Acidswhich may be used for this purpose include for example hydrochloricacid, hydrobromic acid, sulphuric acid, phosphoric acid, fumaric acid,succinic acid, lactic acid, citric acid, tartaric acid, maleic acid ormethanesulphonic acid.

[0136] Moreover, if the new compounds of formula I thus obtained containa carboxy group, they may subsequently, if desired, be converted intothe salts thereof with inorganic or organic bases, particularly forpharmaceutical use into the physiologically acceptable salts thereof.Suitable bases for this purpose include for example sodium hydroxide,potassium hydroxide, cyclohexylamine, ethanolamine, diethanolamine andtriethanolamine.

[0137] The compounds of general formulae II to V used as startingmaterials are known from the literature in some cases or may be obtainedby methods known from the literature or are described in the Examples.For example, the compounds of general formula IV are described in GermanPatent Application 198 24 922.5 of Jun. 4, 1998.

[0138] As already mentioned hereinbefore, the new compounds of generalformula I wherein R₁ denotes a hydrogen atom or a prodrug group havevaluable pharmacological properties, particularly an inhibiting effecton the proliferation of cultivated human cells, especially tumour cells,but also on the proliferation of other cells, particularly endothelialcells, e.g. in angiogenesis.

[0139] For example, the compounds listed in Table 1 were tested fortheir biological properties as follows:

[0140] Test 1

[0141] Inhibition of the Proliferation of Cultivated Human Tumour Cells

[0142] Cells of the Leiomyosarcoma tumour cell line SK-UT-1B ornon-small-cell lung tumour cell line NCI-H460 (obtained from theAmerican Type Culture Collection (ATCC)) were cultivated in MinimumEssential Medium with non-essential amino acids (Gibco), supplementedwith sodium pyruvate (1 mMol), glutamine (2 mMol) and 10% foetal calfserum (Gibco) or RPMI1640 Medium (Gibco) and 10% foetal calf serum(Gibco) and harvested in the logarithmic growth phase. Then the SK-UT-1Bcells were placed in Cytostar® multi-well plates (Amersham) at a densityof 4000 cells per well or 3000 cells per well for NCI-H460 cells andincubated overnight in an incubator. Various concentrations of thecompounds (dissolved in DMSO; final concentration: 0.1%) were added tothe cells. After 48 hours' incubation, ¹⁴C-thymidine (Amersham) wasadded to each well and incubation was continued for a further 24 hours.The quantity of ¹⁴C-thymidine which was incorporated into the tumourcells in the presence of the inhibitor and which represents the numberof cells in the S phase was measured in a Wallace 1450 Microbeta LiquidScintillation Counter. IC₅₀ values for the inhibition of theproliferation (=inhibition of incorporated ¹⁴C-thymidine) werecalculated, correcting for the background radiation. All themeasurements were done twice.

[0143] Test 2

[0144] In Vivo Effects on Tumour-Bearing Nude Mice

[0145] 10⁶ cells [SK-UT-1B, or non-small cell lung tumour NCI-H460(obtained from ATCC)] ina volume os 0.1 ml were injected subcutaneouslyinto male and/or female nude mice (NMRI nu/nu; 25-35 g; N=10-20);alternatively, small fragments of SK-UT-1B or NCI-H460 cell clumps wereimplanted subcutaneously. One to three weeks after injection orimplantation an inhibitor was administered orally (by oesophageal tube)daily for a period of 2 to 4 weeks. The tumour size was measured threetimes a week using a digital sliding gauge. The effect of a compound onthe tumour growth was determined as a percentage inhibition comparedwith a control group treated with placebo. The following Table containsthe results obtained with the in vitro Test 1 (++ denotes <0.01 μM, +denotes 0.01-1.0 μM): Compound Inhibition of SKUT-1B (Example No.)proliferation 2 + 4 ++ 9 + 12 + 20 + 22 + 23 + 31 ++ 36 ++ 42 + 56 ++58 + 66 ++ 70 + 71 + 72 + 80 ++ 88 + 98 + 99 ++ 101 ++ 104 ++ 112 ++117 + 120 ++ 134 ++ 142 + 143 + 144 + 145 + 158 + 164 + 186 ++ 207 +

[0146] In view of their biological properties, the new compounds ofgeneral formula I, their isomers and their physiologically acceptablesalts are suitable for treating conditions characterised by excessive oranomalous cell proliferation.

[0147] Such diseases include (without any claim to completeness): viralinfections (e.g. HIV and Kaposi's sarcoma); inflammation and autoimmunediseases (e.g. colitis, arthritis, Alzheimer's disease,glomerulonephritis and wound healing); bacterial, fungal and/orparasitic infection; leukaemias, lymphoma and solid tumours; skindiseases (e.g. psoriasis); bone diseases; cardiovascular diseases (e.g.restenosis and hypertrophy).

[0148] The new compounds may be used for the short-term or long-termtreatment of the abovementioned conditions, possibly in conjunction withother state-of-the-art compounds such as other cytostatics.

[0149] The dosage required to achieve the desired effect is expedientlyfrom 0.1 to 30 mg/kg, preferably 0.3 to 10 mg/kg, by intravenous routeand 0.1 to 100 mg/kg, preferably 0.3 to 30 mg/kg by oral route, in eachcase 1 to 4 times a day. For this purpose, the compounds of formula Iprepared according to the invention, optionally combined with otheractive substances, may be formulated with one or more inert conventionalcarriers and/or diluents, e.g. with corn starch, lactose, glucose,microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone,citric acid, tartaric acid, water, water/ethanol, water/glycerol,water/sorbitol, water/polyethyleneglycol, propyleneglycol,cetylstearylalcohol, carboxymethylcellulose or fatty substances such ashard fat or suitable mixtures thereof, to produce conventional galenicpreparations such as plain or coated tablets, capsules, powders,suspensions or suppositories or as solutions for injections orinfusions.

[0150] The Examples which follow are intended to illustrate theinvention without restricting it:

[0151] Abbreviations used: CDI N,N'-carbonyldiimidazole DMFdimethylformamide DMSO dimethylsulphoxide TBTUO-(benzotriazol-1-yl)-N,N,N'-N'-bis(tetramethylene)-uroniumhexafluorophosphate THF tetrahydrofuran

[0152] Preparation of the starting compounds:

EXAMPLE I

[0153] 4-[N-Acetyl-N-(2-trifluoracetylaminoethyl)-amino]-aniline

[0154] a. 4-(2-tert.Butoxycarbonylamino-ethylamino)-nitrobenzene

[0155] 4.2 g (29.7 mmol) of N-tert.butoxycarbonyl-ethylenediamine, 5.0 g(31.2 mmol) of 4-fluoro-nitrobenzene and 7.0 g (50.6 mmol) of potassiumcarbonate are stirred in 25 ml of DMSO for 9 hours at 60° C. Aftercooling the mixture is diluted with water and extracted with ethylacetate. The combined organic extracts are dried and evaporated down.The residue is stirred with petroleum ether, decanted off and evaporateddown again. The product is stirred with ether and suction filtered.

[0156] Yield: 3.2 g (38% of theory),

[0157] Melting point: 119° C.

[0158] R_(f) value: 0.5 (silica gel; toluene/ethyl acetate=7:3)C₁₃H₁₉N₃O₄ (281.31)

[0159] Mass spectrum: (M−H)⁻32 280

[0160] b. 4-(2-trifluoroacetylamino-ethylamino)-nitrobenzene

[0161] 1.5 g (5.3 mmol) of4-(2-tert.butoxycarbonylamino-ethylamino)-nitrobenzene are stirred in 15ml of trifluoroacetic acid for 3 hours at ambient temperature. Then 0.8ml (5.7 mmol) of trifluoroacetic acid anhydride are added while coolingwith ice. The reaction is left overnight to come up to ambienttemperature. It is then evaporated down, diluted with water and madealkaline with sodium hydrogen carbonate. The crude product is suctionfiltered and purified by chromatography (silica gel;dichloromethane/methanol=98:2).

[0162] Yield: 1.2 g (81% of theory),

[0163] R_(f) value: 0.5 (silica gel; dichloromethane/methanol=19:1)

[0164] C₁₀H₁₀F₃N₃O₃ (277.21)

[0165] Mass spectrum: (M−H)⁻=276

[0166] c.4-[N-Acetyl-N-(2-trifluoroacetylamino-ethyl)-amino]-nitrobenzene

[0167] 0.6 g (2.1 mmol) of4-(2-trifluoroacetylamino-ethylamino)-nitrobenzene are dissolved in 10ml of glacial acetic acid and after the addition of 2 ml (21.2 mmol) ofacetic acid anhydride stirred for 5 hours at 80° C. and overnight atambient temperature. The solvent is distilled off, the residue is madealkaline with sodium hydrogen carbonate and extracted with ethylacetate. The combined organic extracts are dried and evaporated down.

[0168] Yield: 0.7 g (97% of theory),

[0169] R_(f) value: 0.4 (silica gel; dichloromethane/methanol=19:1)

[0170] C₁₂H₁₂F₃N₃O₄ (319.24)

[0171] Mass spectrum: (M−H)⁻=318

[0172] d. 4-[N-acetyl-N-(2-trifluoroacetylamino-ethyl)-amino]-aniline

[0173] 0.7 g (2.1 mmol) of4-[N-acetyl-N-(2-trifluoroacetylamino-ethyl)-amino]-nitrobenzene aredissolved in 20 ml of methanol and after the addition of 100 mg of 10%palladium on activated charcoal hydrogenated with hydrogen for 3 hours.Then the catalyst is filtered off and evaporated down.

[0174] Yield: 0.6 g (91% of theory),

[0175] R_(f) value: 0.7 (silica gel;dichloromethane/methanol/ammonia=9:1:0.1)

[0176] C₁₂H₁₄F₃N₃O₂ (289.26)

[0177] Mass spectrum: (M−H)⁻=288, (M+Na)⁺=312

[0178] The following compounds were prepared analogously to Example I:

[0179] (1) 4-[N-(2-dimethylamino-ethyl)-N-acetyl-amino]-aniline

[0180] R_(f) value: 0.3 (silica gel;dichloromethane/methanol/ammonia=9:1:0.1)

[0181] C₁₂H₁₉N₃O (221.31)

[0182] Mass spectrum: (M+H)⁺=222

[0183] (2) 4-[N-(2-acetylamino-ethyl)-N-acetyl-amino]-aniline

[0184] R_(f) value: 0.4 (silica gel; ethyl acetate/methanol=8:2)

[0185] C₁₂H₁₇N₃O₂ (235.28)

[0186] Mass spectrum: (M+Na)⁺=258, (M−H)⁻=234

[0187] (3) 4-[N-(2-acetylamino-ethyl)-N-propionyl-amino]-aniline

[0188] R_(f) value: 0.4 (silica gel; ethyl acetate/methanol=9:1)

[0189] (4) [N-(2-propionylamino-ethyl)-N-propionyl-amino]-aniline

[0190] R_(f) value: 0.5 (silica gel; ethyl acetate/methanol=9:1)

[0191] (5)4-{N-[2-(N-acetyl-N-methyl-amino)-ethyl]-N-propionyl-amino}-aniline

[0192] R_(f) value: 0.5 (silica gel;dichloromethane/methanol/ammonia=19:1:0.1)

[0193] C₁₄H₂₁N₃O₂ (263.34)

[0194] Mass spectrum: (M+Na)⁺=286

[0195] (6)4-{N-[2-(N-acetyl-N-methyl-amino)-ethyl]-N-acetyl-amino}-aniline

[0196] R_(f) value: 0.3 (silica gel; ethyl acetate/methanol=9:1)

[0197] C₁₃H₁₉N₃O₂ (249.31)

[0198] Mass spectrum: (M−H)⁻=248, (M+Na)⁺=272

[0199] (7) 4-(dimethylaminocarbonylmethylamino)-aniline

[0200] R_(f) value: 0.6 (silica gel;dichloromethane/methanol/ammonia=9:1:0.1)

[0201] C₁₂H₁₅N₃O (193.25)

[0202] Mass spectrum: (M+H)⁺=194, (M+Na)⁺=216

[0203] (8) 4-(N-ethoxycarbonylmethyl-N-acetyl-amino)-aniline

[0204] R_(f) value: 0.5 (silica gel;dichloromethane/methanol/ammonia=9:1:0.1)

[0205] C₁₂H₁₆N₂O₃ (236.27)

[0206] Mass spectrum: (M−H)⁻=235, (M+Na)⁺=259

[0207] (9) 4-[N-(3-dimethylamino-propyl)-N-propionyl-amino]-aniline

[0208] R_(f) value: 0.2 (silica gel;dichloromethane/methanol/ammonia=8.5:1.5:0.15)

[0209] C₁₄H₂₃N₃O (249.36)

[0210] Mass spectrum: (M−H)⁻=248, (M+H)⁺=250

EXAMPLE II

[0211] 4-[N-(2-benzyloxycarbonylamino-ethyl)-N-acetyl-amino)-aniline

[0212] 450 mg (1.26 mmol) of4-[N-(2-benzyloxycarbonylamino-ethyl)-N-acetyl-amino)-nitrobenzene(prepared analogously to Example I) are dissolved in 20 ml of methanoland after the addition of 100 mg of Lindlar catalyst hydrogenated for 2hours with hydrogen. The catalyst is filtered off, the solution isevaporated down.

[0213] Yield: 410 mg (99% of theory),

[0214] R_(f) value: 0.4 (silica gel; ethyl acetate/dichloromethane=7:3)

[0215] C₁₈H₂₁N₃O₃ (327.38)

[0216] Mass spectrum: (M+Na)⁺=350, (M−H)⁻=326

[0217] The following compounds were prepared analogously to Example II:

[0218] (1)4-{N-[2-(N-benzyl-N-methyl-amino)-ethyl]-N-acetyl-amino}-aniline

[0219] R_(f) value: 0.7 (silica gel; ethylacetate/methanol/ammonia=9:1:0.1)

[0220] C₁₈H₂₃N₃O (297.40)

[0221] Mass spectrum: (M+H)⁺=298, (M−H)⁻=296

[0222] (2)4-{N-[2-(N-benzyl-N-methyl-amino)-ethyl]-N-propionyl-amino}-aniline

[0223] R_(f) value: 0.5 (silica gel;dichloromethane/methanol/ammonia=9:1:0.1)

[0224] C₁₉H₂₅N₃O (311.43)

[0225] Mass spectrum: (M+H)⁺=312

EXAMPLE III

[0226]4-[N-(2-trifluoroacetylamino-ethyl)-N-methylsulphonyl-amino]-aniline

[0227] a.4-(N-ethoxycarbonylmethyl-N-methylsulphonyl-amino)-nitrobenzene

[0228] 20 g (92.5 mmol) of 4-(methylsulphonylamino)-nitroaniline aredissolved in 155 ml of DMSO and while cooling with ice 11.7 (104 mmol)of potassium tert. butoxide are added. After 1 hour 13.5 ml (121 mmol)of ethyl bromoacetate are added. The mixture is stirred for 18 hours atambient temperature and the reaction solution is then poured onto icewater. It is extracted with ethyl acetate. The organic phase is washedwith water, dried and freed from the solvent in vacuo. The residue istriturated with petroleum ether.

[0229] Yield: 27.1 g (97% of theory),

[0230] Melting point: 73-75° C.

[0231] R_(f) value: 0.8 (silica gel; dichloromethane/ethyl acetate=9:1)

[0232] C₁₁H₁₄N₂O₆S (302.31)

[0233] Mass spectrum: (M+Na)⁺=325, (M−H)⁻=301

[0234] b. 4-(N-carboxymethyl-N-methylsulphonyl-amino)-nitrobenzene

[0235] 26.8 g (88.6 mmol) of4-(N-ethoxycarbonylmethyl-N-methylsulphonyl-amino)-nitrobenzene aresuspended in 320 ml of ethanol and combined with 268 ml of 1 N sodiumhydroxide solution. The mixture is stirred for one hour at ambienttemperature and then 268 ml of 1 N hydrochloric acid are added. Theprecipitate formed is suction filtered, washed with a little ethanol andether, and dried in vacuo.

[0236] Yield: 21.9 g (90% of theory),

[0237] Melting point: 215-218° C.

[0238] R_(f) value: 0.6 (silica gel; dichloromethane/methanol/glacialacetic acid=9:1:0.1)

[0239] C_(g)H₁₀N₂O₆S (274.25)

[0240] Mass spectrum: (M−H)⁻=273

[0241] c. 4-(N-aminocarbonylmethyl-N-methylsulphonyl-amino)-nitrobenzene

[0242] 2.5 g (15.4 mmol) of CDI are added to a solution of 3 g (10.9mmol) of 4-(N-carboxymethyl-N-methylsulphonyl-amino)-nitrobenzene in 30ml of DMF. The mixture is stirred for one hour at ambient temperature.Then NH₃ is piped in at 0° C. over a period of 10 min. After 2 hours'stirring at ambient temperature 100 ml of water are added. The mixtureis extracted with ethyl acetate, the organic phase is washed with water,dried over magnesium sulphate and evaporated to dryness. The residue isstirred with water, suction filtered and washed with ether.

[0243] Yield: 2.3 g (78% of theory),

[0244] Melting point: 160° C.

[0245] R_(f) value: 0.5 (silica gel; ethyl acetate/dichloromethane=3:2)

[0246] d. 4-[N-(2-aminoethyl)-N-methylsulphonyl-amino]-nitrobenzene

[0247] 2.3 g (8.4 mmol) of4-(N-aminocarbonylmethyl-N-methylsulphonyl-amino)-nitrobenzene arerefluxed in 35 ml (35 mmol) of borane-THF (1 M solution in THF) 7 hours.Then 30 ml of 6 N hydrochloric acid are added, and the mixture isrefluxed for another 8 hours. The solvent is distilled off, the residueis mixed with water and extracted with ethyl acetate. The aqueous phaseis made alkaline with potassium carbonate and extracted withdichloromethane. The organic phase is separated off, dried andevaporated down.

[0248] Yield: 1.7 g (77% of theory),

[0249] R_(f) value: 0.5 (silica gel;dichloromethane/methanol/ammonia=9:1:0.1)

[0250] C₉H₁₃N₃O₄S (259.29)

[0251] Mass spectrum: (M+H)⁺=260, (M−H)⁻=258

[0252] e.4-[N-(2-trifluoroacetylamino-ethyl)-N-methylsulphonyl-amino]-aniline

[0253] Prepared analogously to Example Ib by reacting4-[N-(2-aminoethyl)-N-methylsulphonyl-amino]-nitrobenzene withtrifluoroacetic acid anhydride in trifluoroacetic acid followed bycatalytic reduction analogously to Example Id with 10%palladium/charcoal in methanol.

[0254] Yield: 76% of theory,

[0255] R_(f) value: 0.6 (silica gel;dichloromethane/methanol/ammonia=9:1:0.1)

[0256] The following compounds were prepared analogously to Example III:

[0257] (1) 4-(N-ethoxycarbonylmethyl-N-ethylsulphonyl-amino)-aniline

[0258] R_(f) value: 0.5 (silica gel; petroleum ether/ethyl acetate=4:6)

[0259] Melting point: 78° C.

[0260] C₁₂H₁₈N₂O₄S (286.35)

[0261] Mass spectrum: (M+Na)⁺=309, (2M+Na)⁺=593

[0262] (2)4-{N-[2-(N-acetyl-N-methyl-amino)-ethyl]-N-methylsulphonyl-amino)-aniline

[0263] R_(f) value: 0.5 (silica gel;dichloromethane/methanol/ammonia=19:1:0.1)

[0264] (3) 4-[N-(2-acetylamino-ethyl)-N-methylsulphonyl-amino]-aniline

[0265] R_(f) value: 0.5 (silica gel;dichloromethane/methanol/ammonia=19:1:0.1)

[0266] C₁₁H₁₇N₃O₃S (271.34)

[0267] Mass spectrum: (M+H)⁺=272, (M+Na)⁺=294

[0268] (4)4-{N-[2-(N-acetyl-N-methyl-amino)-ethyl]-N-ethylsulphonyl-amino}-aniline

[0269] R_(f) value: 0.5 (silica gel;dichloromethane/methanol/ammonia=19:1:0.1)

[0270] Melting point: 140° C.

[0271] C₁₃H₂₁N₃O₃S (299.39)

[0272] Mass spectrum: M⁺=299

[0273] (5) 4-[N-(2-acetylamino-ethyl)-N-ethylsulphonyl-amino)-aniline

[0274] R_(f) value: 0.4 (silica gel;dichloromethane/methanol/ammonia=19:1:0.1)

[0275] C₁₂H₁₉N₃O₃S (285.36)

[0276] Mass spectrum: (M−H)⁻=284, (M+Na)⁺=308

[0277] (6)4-{N-[2-(N-methyl-N-trifluoroacetyl-amino)-ethyl]-N-methylsulphonyl-amino}-aniline

[0278] R_(f) value: 0.5 (silica gel; dichloromethane/ethyl acetate=9:1)

EXAMPLE IV

[0279] 4-[N-(2-dimethylamino-ethyl)-N-phenylsulphonyl-amino]-aniline

[0280] a. N-(2-dimethylamino-ethyl)-phenylsulphonamide

[0281] 2.8 g (30 mmol) of N,N-dimethylethylenediamine are placed in 100ml of dichloromethane and 8.3 ml (60 mmol) of triethylamine. Whilecooling with ice a solution of 3.9 ml (30 mmol) of benzenesulphonic acidchloride in 100 ml of dichloromethane is added dropwise and the mixtureis stirred overnight at ambient temperature. Water is added and themixture is extracted with dichloromethane. The organic phase is driedand evaporated down.

[0282] Yield: 6.8 g (99% of theory), R_(f) value: 0.4 (silica gel;dichloromethane/methanol/ammonia=9:1:0.1)

[0283] C₁₀H₁₆N₂O₂S (228.23)

[0284] Mass spectrum: (M−H)⁻=227, (M+H)⁺=229

[0285] b.4-[N-(2-dimethylamino-ethyl)-N-phenylsulphonyl-amino]-nitrobenzene

[0286] 6.8 g (29.8 mmol) of N-(2-dimethylamino-ethyl)-phenylsulphonamideare dissolved in 100 ml of DMF and combined with 1.3 g (30 mmol) ofsodium hydride (55% in oil). The mixture is stirred for one hour atambient temperature. Then 4.2 g (29.8 mmol) of 4-fluoro-nitrobenzene areadded, and stirring is continued for another 16 hours. After theaddition of 300 ml of water the mixture is extracted with ethyl acetate.The organic phase is washed with water, dried and evaporated down. Theresidue is acidified with 1 N hydrochloric acid and washed with ethylacetate. The aqueous phase is then made basic again with sodiumhydroxide solution and extracted with ethyl acetate. The organic phaseis dried and evaporated down.

[0287] Yield: 6.0 g (58% of theory),

[0288] R_(f) value: 0.4 (silica gel;dichloromethane/methanol/ammonia=9:1:0.1)

[0289] C₁₆H₁₉N₃O₄S (349.41)

[0290] Mass spectrum: (M−H)⁻=348, (M+H)⁺=350

[0291] c. 4-[N-(2-dimethylaminoethyl)-N-phenylsulphonyl-amino]-aniline

[0292] Prepared analogously to Example Id by catalytic hydrogenation of6 g (17.2 mmol) of4-[N-(2-dimethylamino-ethyl)-N-phenylsulphonyl-amino]-nitrobenzene.

[0293] Yield: 5.5 g (99% of theory),

[0294] R_(f) value: 0.5 (silica gel;dichloromethane/methanol/ammonia=9:1:0.1)

[0295] C₁₆H₂₁N₃O₂S (319.43)

[0296] Mass spectrum: (M+H)⁺=320

[0297] The following compounds were prepared analogously to Example IV:

[0298] (1) 4-[N-(2-dimethylamino-ethyl)-N-propylsulphonyl-amino]-aniline

[0299] R_(f) value: 0.4 (silica gel;dichloromethane/methanol/ammonia=9:1:0.1)

[0300] C₁₃H₂₃N₃O₂S (285.41)

[0301] Mass spectrum: (M+H)⁺=286, (M−H)⁻=284

[0302] (2) 4-[N-(2-dimethylamino-ethyl)-N-butylsulphonyl-amino]-aniline

[0303] R_(f) value: 0.4 (silica gel;dichloromethane/methanol/ammonia=9:1:0.1)

[0304] C₁₄H₂₅N₃O₂S (299.43)

[0305] Mass spectrum: (M+H)⁺=300

[0306] (3)4-[N-(3-dimethylamino-propyl)-N-methylsulphonyl-amino]-aniline

[0307] Melting point: 112-113° C.

[0308] R_(f) value: 0.4 (silica gel;dichloromethane/methanol/ammonia=9:1:0.1)

[0309] C₁₂H₂₁N₃O₂S (271.38)

[0310] Mass spectrum: (M+H)⁺=272, (M+Na)⁺=294

[0311] (4) 4-[N-(2-dimethylamino-ethyl)-N-benzylsulphonyl-amino]-aniline

[0312] R_(f) value: 0.3 (silica gel;dichloromethane/methanol/ammonia=9:1:0.1)

[0313] C₁₇H₂₃N₃O₂S (333.46)

[0314] Mass spectrum: (M+H)⁺=334, (M+Na)⁺=356

[0315] (5)3-chloro-4-[N-(2-dimethylamino-ethyl)-N-methylsulphonyl-amino]-aniline

[0316] Melting point: 145-148° C.

[0317] R_(f) value: 0.5 (silica gel;dichloromethane/ethanol/ammonia=5:1:0.01)

[0318] C₁₁H₁₈ClN₃O₂S (291.80)

[0319] Mass spectrum: (M+H)⁺=294, 292, (M−H)⁻=292, 290

[0320] (6)3-amino-4-[N-(2-dimethylamino-ethyl)-N-methylsulphonyl-amino]-aniline

[0321] R_(f) value: 0.3 (silica gel;dichloromethane/methanol/ammonia=9:1:0.1)

[0322] C₁₁H₂₀N₄O₂S (272.37)

[0323] Mass spectrum: (M+H)⁺=273

[0324] (7) 4-[N-(2-dimethylamino-ethyl)-N-methylsulphonyl-amino]-aniline

[0325] R_(f) value: 0.3 (silica gel;dichloromethane/methanol/ammonia=9:1:0.1)

[0326] Melting point: 147-148° C.

[0327] C₁₁H₁₉N₃O₂S (257.36)

[0328] Mass spectrum: (M+H)⁺=258, (M+Na)⁺=280

EXAMPLE V

[0329] 3-[N-(2-dimethylamino-ethyl)-N-methylsulphonyl-amino]-aniline

[0330] a.3-[N-(2-dimethylamino-ethyl)-N-methylsulphonyl-amino]-nitrobenzene

[0331] 5 g (23.1 mmol) of 3-methylsulphonylamino-nitrobenzene aredissolved in 50 ml of DMSO and combined with 6.5 g (58 mmol) ofpotassium tert. butoxide while cooling with ice. The solution thusobtained is added dropwise to a solution of 5 g (34.7 mmol) of2-chloro-N,N-dimethyl-ethylamine in 30 ml of DMSO. The mixture isstirred for 2 hours at ambient temperature and then heated for 6 hoursto 100° C. After cooling to ambient temperature 400 ml of water areadded. The mixture is extracted with ethyl acetate. Water and 1 Nhydrochloric acid are added to the combined organic phases until an acidreaction is obtained. The aqueous phase is washed with ethyl acetate.Then the aqueous phase is made alkaline with sodium carbonate and theproduct is extracted with ethyl acetate. Drying the combined organicphases over magnesium sulphate and eliminating the solvents in vacuoyields the product as a red oil.

[0332] Yield: 2.07 g (31% of theory),

[0333] R_(f) value: 0.3 (silica gel; ethyl acetate/methanol=4:1)

[0334] C₁₁H₁₇N₃O₄S (287.34)

[0335] Mass spectrum: (M−H)⁻=286, (M+H)⁺=288

[0336] b. 3-[N-(2-dimethylamino-ethyl)-N-methylsulphonyl-amino]-aniline

[0337] Prepared analogously to Example Id by catalytic hydrogenation of1.9 g (6.8 mmol) of3-[N-(2-dimethylamino-ethyl)-N-methylsulphonyl-amino]-nitrobenzene overpalladium/charcoal.

[0338] Yield: 1.8 g (99% of theory),

[0339] R_(f) value: 0.3 (silica gel; ethylacetate/methanol/NH₄OH=8:2:0.1)

[0340] C₁₁H₁₉N₃O₂S (257.36)

[0341] Mass spectrum: (M−H)⁻=256, (M+H)⁺=258

EXAMPLE VI

[0342] 4-(4-benzyl-piperazinomethyl)-aniline

[0343] a. 4-(4-tert.butoxycarbonyl-piperazinomethyl)-nitrobenzene

[0344] A mixture of 10.6 g (57 mmol) ofN-tert.butoxycarbonyl-piperazine, 10.8 g (62.7 mmol) of4-nitrobenzylchloride, 23.8 ml (171 mmol) of triethylamine in 100 ml ofdichloromethane is stirred for 12 hours at 70° C. After diluting withwater the organic phase is separated off, dried and evaporated down.

[0345] Yield: 19 g (99% of theory),

[0346] Melting point: 83-84° C.

[0347] R_(f) value: 0.7 (silica gel;dichloromethane/methanol/ammonia=9:1:0.1)

[0348] C₁₆H₂₃N₃O₄ (321.38)

[0349] Mass spectrum: (M+H)⁺=322, (M−H)⁻=320

[0350] b. 4-piperazinomethyl-nitrobenzene-dihydrochloride

[0351] 6.4 g (20 mmol) of4-(4-tert.butoxycarbonyl-piperazinomethyl)-nitrobenzene are dissolved in20 ml of dichloromethane and combined with 40 ml of ethyl acetate/HCl.The reaction solution is diluted with ether, the precipitate formed issuction filtered as a crude product and then reacted further.

[0352] Yield: 5.4 g (92% of theory),

[0353] Melting point: 257-258° C.

[0354] R_(f) value: 0.3 (silica gel;dichloromethane/methanol/ammonia=9:1:0.1)

[0355] c. 4-(4-benzylpiperazinomethyl)-nitrobenzene

[0356] The free base is produced from 1.5 g (5 mmol) of4-piperazinomethyl-nitrobenzene-dihydrochloride by dissolving in 25 mlof 1 N sodium hydroxide solution, extracting with ethyl acetate and theneliminating the solvent in vacuo. The solid thus obtained is combinedwith 2.5 ml of 2 N acetic acid, 0.5 ml (5.5 mmol) of benzaldehyde and 50ml of methanol and, after the addition of 0.7 g (5 mmol) of sodiumcyanoborohydride, stirred for 2 hours. Then the pH is adjusted to acidwith 1 N hydrochloric acid and the reaction solution is washed withether. The aqueous phase is then made basic with sodium hydroxidesolution. The product is extracted with ether, the combined etherextracts are dried and the solvent is eliminated in vacuo.

[0357] Yield: 1.3 g (84% of theory),

[0358] R_(f) value: 0.6 (silica gel;dichloromethane/methanol/ammonia=9:1:0.1)

[0359] C₁₈H₂₁N₃O₂ (311.39)

[0360] Mass spectrum: (M+H)⁺=312

[0361] d. 4-(4-benzylpiperazinomethyl)-aniline

[0362] Prepared analogously to Example Id by catalytic hydrogenation of1.3 g (4.2 mmol) of 4-(4-benzylpiperazinomethyl)-nitrobenzene overpalladium/charcoal.

[0363] Yield: 1.2 g (87% of theory),

[0364] Melting point: 88-89° C.

[0365] C₁₈H₂₃N₃ (281.4)

[0366] Mass spectrum: (M+H)⁺=282

EXAMPLE VII

[0367] 4-(4-tert.butoxycarbonyl-piperazinomethyl)-aniline

[0368] a. 4-(4-tert.butoxycarbonyl-piperazinomethyl)-nitrobenzene

[0369] 10.6 g (57 mmol) of N-tert.butoxycarbonyl-piperazine aredissolved in 100 ml of dichloromethane and combined with 10.7 g (63mmol) of 4-nitrobenzylchloride and 24 ml (171 mmol) of triethylamine.The mixture is refluxed for 12 hours. After cooling to ambienttemperature the reaction solution is washed several times with water.The organic phase is dried over magnesium sulphate and then evaporatedto dryness.

[0370] Yield: 17 g (99%) of theory Melting point: 83-84° C.

[0371] R_(f) value: 0.7 (silica gel;dichloromethane/methanol/ammonia=9:1:0.1)

[0372] C₁₆H₂₃N₃O₄ (321.38)

[0373] Mass spectrum: (M+H)⁺=322, (M−H)⁻=320

[0374] b. 4-(4-tert.butoxycarbonyl-piperazinomethyl)-aniline

[0375] Prepared analogously to Example Id by catalytic hydrogenation of4-(4-tert.butoxycarbonyl-piperazinomethyl)-nitrobenzene with Raneynickel in ethyl acetate/methanol (1:1).

[0376] Melting point: 106-107° C.

[0377] R_(f) value: 0.6 (silica gel;dichloromethane/methanol/ammonia=9:1:0.1)

[0378] C₁₆H₂₅N₃O₂ (291.39)

[0379] Mass spectrum: (M+H)⁺=292, (M+Na)⁺=314

[0380] The following compounds were prepared analogously to Example VII:

[0381] (1) 4-(pyrrolidin-1-yl-methyl)-aniline

[0382] R_(f) value: 0.2 (silica gel;dichloromethane/methanol/NH₄OH=5:1:0.01)

[0383] Melting point: 48-50° C.

[0384] (2) 4-(4-methylpiperazinomethyl)-aniline

[0385] Melting point: 94-95° C.

[0386] R_(f) value: 0.2 (silica gel;dichloromethane/methanol/ammonia=9:1:0.1)

[0387] C₁₂H₁₉N₃ (205.31)

[0388] Mass spectrum: (M+H)⁺=206

[0389] (3) 3-(dimethylaminomethyl)-aniline

[0390] R_(f) value: 0.7 (silica gel; ethyl acetate)

[0391] Melting point: 43-46° C.

[0392] (4) 4-(dimethylaminomethyl)-aniline

[0393] R_(f) value: 0.13 (silica gel; ethyl acetate/ethanol=8:2)

[0394] (5) 4-(2-dimethylamino-ethyl)-aniline

[0395] R_(f) value: 0.3 (silica gel;dichloromethane/methanol/ammonia=19:1:0.1)

[0396] Melting point: 40° C.

[0397] C₁₀H₁₆N₂ (164.25)

[0398] Mass spectrum: (M+H)⁺=165

[0399] (6) 4-(N-benzyl-N-methyl-aminomethyl)-aniline

[0400] R_(f) value: 0.5 (silica gel;dichloromethane/methanol/ammonia=10:1:0.01)

[0401] Melting point: 48-50° C.

[0402] C₁₅H₁₈N₂ (226.32)

[0403] Mass spectrum: (M+H)⁺=227

[0404] (7) 4-piperidinomethyl-aniline

[0405] R_(f) value: 0.2 (silica gel;dichloromethane/methanol/ammonia=9:1:0.1)

[0406] Melting point: 88-89° C.

[0407] (8) 4-(2,6-dimethylpiperidino-methyl)-aniline

[0408] R_(f) value: 0.3 (silica gel;dichloromethane/methanol/ammonia=5:1:0.01)

[0409] Melting point: 112-115° C.

[0410] (9) 4-(N-ethyl-N-methyl-aminomethyl)-aniline

[0411] R_(f) value: 0.4 (silica gel;dichloromethane/methanol/ammonia=10:1:0.1)

[0412] C₁₀H₁₆N₂ (164.25)

[0413] Mass spectrum: (M+H)⁺=165

[0414] (10)4-[4-(3-trifluoromethylcarbonylamino-propyl)-piperidinomethyl]-aniline

[0415] R_(f) value: 0.4 (silica gel;dichloromethane/methanol/ammonia=10:1:0.1)

[0416] C₁₇H₂₄F₃N₃O (343.40)

[0417] Mass spectrum: (M+H)⁺=344

[0418] (11) 4-(N-tert.butoxycarbonyl-N-propyl-aminomethyl)-anilineC₁₅H₂₄N₂O₂ (264.37)

[0419] Mass spectrum: (M+Na)⁺=287

[0420] (12) 4-(N-tert.butoxycarbonyl-N-butyl-aminomethyl)-aniline

[0421] R_(f) value: 0.19 (silica gel; dichloromethane/methanol=50:1)

[0422] C₁₆H₂₆N₂O₂ (278.40)

[0423] Mass spectrum: (M+Na)⁺=301

[0424] (13) 4-(N-tert.butoxycarbonyl-N-ethyl-aminomethyl)-aniline

[0425] Melting point: 85° C.

[0426] R_(f) value: 0.3 (silica gel; dichloromethane/methanol/=50:1)

[0427] C₁₄H₂₂N₂O₂ (250.34)

[0428] Mass spectrum: (M+Na)⁺=273

EXAMPLE VII

[0429] 4-(2-oxopiperidinomethyl)-aniline

[0430] 6.4 g (42 mmol) of 4-nitrobenzaldehyde are dissolved in 150 ml ofmethanol and combined with 4.9 g (42 mmol) of 5-aminovaleric acid and1.8 g (29 mmol) of sodium cyanoborohydride. The mixture is stirred for18 hours at ambient temperature and then carefully mixed with 20 ml ofconc. hydrochloric acid. The solvent is eliminated in vacuo, the residueis taken up in water and extracted with dichloromethane. The residueobtained after evaporation is chromatographed on silica gel(dichloromethane/methanol, 4:1). A mixture of methyl5-(4-nitrobenzylamino)-pentanoate and4-(2-oxopiperidinomethyl)-nitrobenzene is obtained which is dissolved in100 methanol and combined with 50 ml of 1 N sodium hydroxide solution.The mixture is stirred for one hour at ambient temperature, 50 ml of 1 Nhydrochloric acid are added and the reaction solution is evaporated downto 100 ml. The aqueous phase thus obtained is extracted withdichloromethane. The combined organic phases are dried over sodiumsulphate and evaporated to dryness.

[0431] The residue is hydrogenated analogously to Example Id over Raneynickel in methanol under a hydrogen atmosphere of 3 bar for 11 hours.

[0432] Total yield: 2.2 g (26% of theory),

[0433] R_(f) value: 0.63 (silica gel; dichloromethane/methanol=9:1)

EXAMPLE IX

[0434] 4-(N-piperidinomethylcarbonyl-N-methyl-amino)-aniline

[0435] a. 4-(N-bromomethylcarbonyl-N-methyl-amino)-nitrobenzene

[0436] 23.5 g (0.15 mol) of N-methyl-4-nitroaniline are dissolved in 400ml of dioxane and combined with 22.2 g (0.3 mol) of lithium carbonate.Then 32.2 g (0.18 mol) of bromoacetylbromide are added dropwise in sucha way that the internal temperature does not exceed 33° C. After 18hours' stirring the reaction solution is evaporated down to 100 ml,combined with 500 ml of water and stirred for 1 hour. The precipitateformed is suction filtered, washed with water and dried. The crudeproduct is stirred in 400 ml of ethyl acetate at 40° C. Then theinsoluble matter is filtered off, the solution is evaporated down andthe solid residue is triturated with ether.

[0437] Yield: 35 g (83% of theory),

[0438] Melting point: 85-87° C.

[0439] b. 4-(N-piperidinomethylcarbonyl-N-methyl-amino)-nitrobenzene

[0440] 5.4 g (20 mmol) of4-(N-bromomethylcarbonyl-N-methyl-amino)-nitrobenzene are dissolved in100 ml of acetone and combined with 5.5 g (40 mmol) of potassiumcarbonate. 3 ml (30 mmol) of piperidine are slowly added dropwise andthe mixture is stirred for 18 hours at ambient temperature. The reactionsolution is filtered, and the filtrate is evaporated to dryness. Theresidue is dissolved in ethyl acetate, washed with water, dried overmagnesium sulphate and evaporated to dryness.

[0441] Yield: 5.6 g (99% of theory).

[0442] c. 4-(N-piperidinomethylcarbonyl-N-methyl-amino)-aniline

[0443] Prepared analogously to Example Id by catalytic hydrogenation of4-(N-piperidinomethylcarbonyl-N-methyl-amino)-nitrobenzene in methanolover palladium/charcoal.

[0444] Yield 4.95 g (99% of theory)

EXAMPLE X

[0445] 4-(tert.butoxycarbonylaminomethyl)-aniline

[0446] 20 g (164 mmol) of 4-aminobenzylamine and 20.2 g (210 mmol) oftriethylamine are dissolved in 100 ml of dioxane and 50 ml of water.35.8 g (165 mmol) of di-tert.butyl-dicarbonate dissolved in 60 ml ofdioxane are added to this solution while cooling with ice and theresulting mixture is stirred for 18 hours at ambient temperature. Thenthe solvent is distilled off in vacuo, the residue is distributed inethyl acetate/water. The combined organic extracts are freed fromsolvent in vacuo. The crude product is heated in 200 ml of petroleumether, cooled slowly with vigorous stirring and the crystalline productis removed by suction filtering.

[0447] Yield: 34.8 g (96% of theory),

[0448] Melting point: 77-78° C.

EXAMPLE XI

[0449] 4-(1H-imidazol-2-yl)-aniline

[0450] 7.2 g (50 mmol) of 2-phenylimidazol are dissolved in 100 ml ofconc. sulphuric acid. While cooling with ice 5.0 g (62 mmol) of ammoniumnitrate are added in batches and the mixture is stirred for 2.5 hours.The reaction solution is then poured onto ice, made basic with conc.ammonia and the crystalline product is suction filtered. The nitrocompound thus obtained is catalytically hydrogenated analogously toExample Id in DMF over palladium/charcoal.

[0451] Yield: 24% of theory,

[0452] R_(f) value: 0.4 (silica gel;dichloromethane/methanol/ammonia=9:1:0.1)

EXAMPLE XII

[0453] Pyridine-2-sulphonic Acid Chloride

[0454] 5.0 g (45 mmol) of pyridine-2-thiol are dissolved in 40 ml ofconc. hydrochloric acid. While the solution is cooled with ice, chlorinegas is piped in over a period of 2.5 hours. In order to destroy anyexcess gas a washing bottle containing 1 N sodium thiosulphate solutionis attached. Then the reaction solution is poured onto ice water andextracted with ether and dichloromethane. The organic phases arecombined, dried and freed from solvent in vacuo. The crude product isfurther reacted immediately.

[0455] Yield: 8 g (100% of theory).

EXAMPLE XIII

[0456] Pyridine-3-sulphonic Acid Chloride Hydrochloride

[0457] 1 g (6.3 mmol) of pyridine-3-sulphonic acid and 1.4 g (6.7 mmol)of phosphorus pentachloride are stirred for 2 hours at 150° C. Aftercooling, excess phosphorus pentachloride is eliminated in vacuo. Thecrude product is further reacted immediately.

[0458] Yield: 1.2 g (91% of theory).

[0459] Preparation of the end products:

EXAMPLE 1

[0460](Z)-3-{1-[4-(N-acetyl-N-(2-aminoethyl)-amino)-phenylamino]-1-phenyl-methylidene}-5-phenylsulphonylamino-2-indolinone

[0461] a. 1-acetyl-2-indolinone

[0462] 13.3 g (0.1 mol) of 2-indolinone and 30 ml of acetic anhydrideare stirred for 3 hours at 170° C. After cooling the mixture is combinedwith 150 ml of ice water, the crystalline product is suction filtered,washed with water and dried.

[0463] Yield: 16.6 g (95% of theory),

[0464] Melting point: 129-130° C.

[0465] b. 1-acetyl-5-nitro-2-indolinone

[0466] 0.5 g (2.8 mmol) of 1-acetyl-2-indolinone are placed in 4 ml ofconc. sulphuric acid. At a temperature of −10 to −5° C., 0.3 g (3.4mmol) of ammonium nitrate are added in batches. After 45 minutes themixture is poured onto ammonia/ice water, the crystalline precipitate issuction filtered, washed with water and dried. The crude product isrecrystallised from 70 ml of cyclohexane.

[0467] Yield: 0.2 g (32% of theory),

[0468] Melting point: 150-157° C.

[0469] R_(f) value: 0.7 (silica gel; cyclohexane/ethyl acetate=4:6)

[0470] c. 1-acetyl-5-amino-2-indolinone

[0471] 30.0 g (136 mmol) of 1-acetyl-5-nitro-2-indolinone are dissolvedin a mixture of 650 ml of dichloromethane and 650 ml of methanol andafter the addition of 5 g of 10% palladium on activated charcoal themixture is hydrogenated for 45 minutes with hydrogen. Then the catalystis filtered off and evaporated down.

[0472] Yield: 22.4 g (87% of theory),

[0473] Melting point: 177° C.

[0474] R_(f) value: 0.7 (silica gel; ethyl acetate)

[0475] C₁₀H₁₀N₂O₂ (190.20)

[0476] Mass spectrum: (M−H)⁻=189, (M+Na)⁺=213

[0477] d. 1-acetyl-5-phenylsulphonylamino-2-indolinone

[0478] 20.0 g (105 mmol) of 1-acetyl-5-amino-2-indolinone are placed in200 ml of pyridine, combined with 15.3 ml (120 mmol) of benzenesulphonicacid chloride while cooling with ice and stirred for 2 hours. Then themixture is poured onto 1.81 of water and suction filtered. The crudeproduct is stirred into acetone, suction filtered and dried.

[0479] Yield: 30.5 g (88% of theory),

[0480] Melting point: 245° C.

[0481] R_(f) value: 0.5 (silica gel; dichloromethane/ethyl acetate=9:1)

[0482] C₁₆H₁₄N₂O₄S (330.37)

[0483] Mass spectrum: (M−H)⁻=329, (M+Na)⁺=353

[0484] e.1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5-(N-acetyl-N-phenylsulphonyl-amino)-2-indolinone

[0485] 8.0 g (24.2 mmol) of 1-acetyl-5-phenylsulphonylamino-2-indolinoneare dissolved in 150 ml of acetic anhydride and after the addition of 20ml (88.1 mmol) of triethyl orthobenzoate refluxed for 6 hours. Thesolvent is distilled off, the residue is triturated with ether, suctionfiltered and dried.

[0486] Yield: 7.8 g (64% of theory),

[0487] Melting point: 237° C.

[0488] R_(f) value: 0.7 (silica gel; dichloromethane/ethyl acetate=19:1)

[0489] C₂₇H₂₄N₂O₆S (504.57)

[0490] Mass spectrum: M⁺=504

[0491] f.(Z)-3-{1-[4-(N-acetyl-N-(2-aminoethyl)-amino)-phenylamino]-1-phenyl-methylidene}-5-phenylsulphonylamino-2-indolinone

[0492] A mixture of 0.5 g (1 mmol) of1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5-(N-acetyl-N-phenylsulphonyl-amino)-2-indolinoneand 0.3 g (1.2 mmol) of4-[N-acetyl-N-(2-trifluoroacetylamino-ethyl)-amino]-aniline are stirredin 5 ml of DMF for 6 hours at 120° C. After cooling to ambienttemperature 5 ml of methanol and 3 ml (6 mmol) of 2 N sodium hydroxidesolution are added, and the mixture is stirred for 30 minutes. Thereaction mixture is diluted with 50 ml of water and the crystallineprecipitate is suction filtered and dried. The residue ischromatographed on silica gel(dichloromethane/methanol/ammonia=9:1:0.1).

[0493] Yield: 0.3 g (49% of theory),

[0494] Melting point: 216° C.

[0495] R_(f) value: 0.3 (silica gel;dichloromethane/methanol/ammonia=9:1:0.1)

[0496] C₃₁H₂₉N₅O₄S (567.67)

[0497] Mass spectrum: (M−H)⁻=566, (M+H)⁺=568

EXAMPLES 2 to 97

[0498] Using the intermediate products prepared in Examples I to XIII,the compounds of formula IA of Examples 2 to 97 listed in Table I areprepared analogously to Example I. TABLE I (IA),

Melting point Example R₂ R₇ R₉ chemical name (° C.) phenylN-(2-aminoethyl)-N- H (Z)-3-{1-[4-(N-(2-aminoethyl)-N-methylsulphonyl-245 methylsulphonyl- amino)-phenylamino]-1-phenyl-methylidene}-5- aminophenylsulphonylamino-2-indolinone phenyl N-(2-methylamino- H(Z)-3-{1-[4-(N-(2-methylamino-ethyl)-N- 227-229 ethyl)-N-methylsulphonyl-amino)-phenylamino]-1-phenyl- methylsulphonyl-methylidene}-5-phenylsulphonylamino-2-indolinone amino phenylN-(2-dimethylamino- H (Z)-3-{1-[4-(N-(2-dimethylaminoethyl)-N- 168-169ethyl)-N- phenylsulphonyl-amino)-phenylamino)-1-phenyl- phenylsulphonyl-methylidene}-5-phenylsulphonylamino-2-indolinone amino phenylN-(2-dimethylamino- H (Z)-3-{1-[4-(N-(2-dimethylamino-ethyl)-N- 137-138ethyl)-N- propylsulphonyl-amino)-phenylamino]-1-phenyl- propylsuphonyl-methylidene}-5-phenylsulphonylamino-2-indolinone amino phenylN-(2-dimethylamino- H (Z)-3-{1-[4-(N-(2-dimethylamino-ethyl)-N- 197-198ethyl)-N- butylsulphonyl-amino)-phenylamino]-1-phenyl-butylsulphonyl-amino methylidene}-5-phenylsulphonylamino-2-indolinonephenyl 4-benzyl-piperazino- H (Z)-3-{1-[4-(4-benzyl-piperazinomethyl)-130 methyl phenylamino]-1-phenyl-methylidene}-5- (decomp.)phenylsulphonylamino-2-indolinone phenyl N-acetyl-N-(2-benzyl- H(Z)-3-{1-[4-(N-acetyl-N-(2-benzyloxycarbonylamino- 180 oxycarbonylamino-ethyl)-amino)-phenylamino]-1-phenyl-methylidene}-5- ethyl)-aminophenylsulphonyl-amino-2-indolinone phenyl 4-methylpiperazino- H(Z)-3-{1-[4-(4-methylpiperazinomethyl)- 243-244 methylphenylamino]-1-phenyl-methylidene}-5- phenylsulphonylamino-2-indolinonephenyl morpholinomethyl H (Z)-3-{1-[4-(morpholinomethyl)-phenylamino]-1-243-244 phenyl-methylidene}-5-phenylsulphonylamino-2- indolinone phenyl2- H (Z)-3-{1-[4-(2-oxopiperidinomethyl)-phenylamino]-1- 311-312oxopiperidinomethyl phenyl-methylidene) -5-phenylsulphonylamino-2-indolinone phenyl pyrrolidin-1-ylmethyl H(Z)-3-{1-[4-(pyrrolidin-1-ylmethyl)-phenylamino]-1- 228-229phenyl-methylidene}-5-phenylsulphonylamino-2- indolinone phenyl4-tert.butoxycarbonyl- H(Z)-3-{1-[4-(4-tert.butoxycarbonyl-piperazinomethyl)- 160-161piperazinomethyl phenylamino]-1-phenyl-methylidene}-5-phenylsulphonylamino-2-indolinone phenyl N-methyl-N-formyl- H(Z)-3-{1-[4-(N-methyl-N-formyl-amino)- 315-317 aminophenylamino]-1-phenyl-methylidene}-5- phenylsulphonylamino-2-indolinonephenyl tert.butoxycarbonyl- H(Z)-3-[1-(4-tert.butoxycarbonylamino-phenylamino)-1- 96-98 aminophenyl-methylidene]-5-phenylsulphonylamino-2- indolinone phenylN-methyl-N- H (Z)-3-{1-[4-(N-methyl-N-propionyl-amino)- 208-210propionyl-amino phenylamino]-1-phenyl-methylidene}-5-phenylsulphonylamino-2-indolinone phenyl acetylamino H(Z)-3-[1-(4-acetylamino-phenylamino)-1-phenyl- 245-247methylidene]-5-phenylsulphonylamino-2-indolinone phenyl N-methyl-N- H(Z)-3-{1-[4-(N-methyl-N-ethylsulphonyl-amino)- 278-280ethylsulphonyl-amino phenylamino]-1-phenyl-methylidene}-5-phenylsulphonylamino-2-indolinone phenyl propionylamino H(Z)-3-[1-(4-propionylamino-phenylamino)-1-phenyl- 254-256methylidene]-5-phenylsulphonylamino-2-idolinone phenylN-methyl-N-acetyl- H (Z)-3-{1-[4-(N-methyl-N-acetyl-amino)- 283-285amino phenylamino]-1-phenyl-methylidene}-5-phenylsulphonylamino-2-indolinone phenyl N-acetyl-N-[2-(N- H(Z)-3-{1-[4-(N-acetyl-N-(2-(N-benzyl-N-methyl- 237 benzyl-N-methyl-amino)-ethyl)-amino)-phenylamino]-1-phenyl- amino)-ethyl]-aminomethylidene}-5-phenylsulphonylamino-2-indolinone phenyl H H(Z)-3-(1-phenylamino-1-phenyl-methylidene)-5- 283phenylsulphonylamino-2-indolinone phenyl chloro H(Z)-3-[1-(4-chlorophenylamino)-1-phenyl- 295methylidene]-5-phenylsulphonylamino-2-indolinone phenylN-(2-dimethylamino- H (Z)-3-{1-[4-(N-(2-dimethylamino-ethyl)-N- 234ethyl)-N- methylsulphonyl-amino)-phenylamino]-1-phenyl- methylsulphonyl-methylidene}-5-phenylsulphonylamino-2-indolinone amino phenylN-(2-dimethylamino- H (Z)-3-{1-[4-(N-(2-dimethylamino-ethyl)-N-acetyl-202 ethyl)-N-acetyl-amino amino)-phenylamino]-1-phenyl-methylidene}-5-phenylsulphonylamino-2-indolinone phenyl N-piperidinomethyl- H(Z)-3-{1-[4-(N-piperidinomethylcarbonyl-N-methyl- 269 carbonyl-N-methyl-amino)-phenylamino]-1-phenyl-methylidene}-5- aminophenylsulphonylamino-2-indolinone phenyl H N-(2-(Z)-3-{1-[3-(N-(2-dimethylamino-ethyl)-N- 140 dimethylamino-methylsulphonyl-amino)-phenylamino]-1-phenyl- ethyl)-N-methyl-methylidene}-5-phenylsulphonylamino-2-indolinone sulphonyl-amino phenylH dimethylamino- (Z)-3-[1-(3-dimethylaminomethyl-phenylamino)-1- 140methyl phenyl-methylidene]-5-phenylsulphonylamino-2- indolinone phenylN-(2-acetylamino- H (Z)-3-{1-[4-(N-(2-acetylamino-ethyl)-N-acetyl- 229ethyl)-N-acetyl-amino amino)-phenylamino]-1-phenyl-methylidene}-5-phenylsulphonylamino-2-indolinone phenyl N-(2-acetylamino- H(Z)-3-{1-[4-(N-(2-acetylamino-ethyl)-N-propionyl- 278ethyl)-N-propionyl- amino)-phenylamino]-1-phenyl-methylidene}-5- aminophenylsulphonylamino-2-indolinone phenyl N-(2-propionylamino- H(Z)-3-{1-[4-(N-(2-propionylamino-ethyl)-N-propionyl- 280ethyl)-N-propionyl- amino)-phenylamino]-1-phenyl-methylidene}-5- aminophenylsulphonylamino-2-indolinone phenyl N-[2-(N-acetyl-N- H(Z)-3-{1-[4-(N-(2-(N-acetyl-N-methyl-amino)-ethyl)- 180methyl-amino)-ethyl]- N-methylsulphonyl-amino)-phenylamino]-1-phenyl-(decomp.) N-methylsulphonyl-methylidene}-5-phenylsulphonylamino-2-indolinone amino phenylN-(2-acetylamino- H (Z)-3-{1-[4-(N-(2-acetylamino-ethyl)-N- 171ethyl)-N- methylsulphonyl-amino)-phenylamino]-1-phenyl- methylsulphonyl-methylidene}-5-phenylsulphonylamino-2-indolinone amino] phenyl4-{N-[2-(N-acetyl-N- H(Z)-3-{1-[4-(N-(2-(N-acetyl-N-methyl-amino)-ethyl)- 216methyl-amino)-ethyl] N-ethylsulphonyl-amino)-phenylamino]-1-phenyl-N-ethylsulphonyl- methylidene}-5-phenylsulphonylamino-2-indolinone aminophenyl cyano H (Z)-3-[1-(4-cyanophenylamino)-1-phenyl- 291-293methylidene]-5-phenylsulphonylamino-2-indolinone phenyldimethylaminomethyl H (Z)-3-[1-(4-dimethylaminomethyl-phenylamino)-1-255-256 phenyl-methylidene]-5-phenylsulphonylaniino-2- indole phenyl2-dimethylamino- H (Z)-3-[1-(4-(2-dimethylamino-ethyl)-phenylamino)-1-302-303 ethyl phenyl-methylidene]-5-phenylsulphonylamino-2- indolinonephenyl N-(2-acetylamino- H (Z)-3-{1-[4-(N-(2-acetylamino-ethyl)-N- 158ethyl)-N- ethylsulphonyl-amino)-phenylamino]-1-phenyl-ethylsulphonyl-amino methylidene}-5-phenylsulphonylamino-2-indolinonephenyl acetylaminomethyl H (Z)-3-[1-(4-acetylaminomethyl-phenylamino)-1-289-290 phenyl-methylidene]-5-phenylsulphonylamino-2- indolinone phenylN-[2-(N-acetyl-N- H (Z)-3-{1-[4-(N-(2-(N-acetyl-N-methyl-amino)-ethyl)-297 methyl-amino)-ethyl]- N-acetyl-amino)-phenylamino]-1-phenyl-N-acetyl-amino methylidene}-5-phenylsulphonylamino-2-indolinone phenylmethylsulphonylamino H (Z)-3-[1-(4-methylsulphonylamino-phenylamino)-1-258-260 phenyl-methylidene]-5-phenylsulphonylamino-2- indolinone phenylN-methyl-N- H (Z)-3-[1-(4-(N-methyl-N-methylsulphonyl-amino)- 306-308methylsulphonyl- phenylamino)-1-phenyl-methylidene]-5- aminophenylsulphonylamino-2-indolinone phenyl ethylsulphonylamino H(Z)-3-[1-(4-ethylsulphonylamino-phenylamino)-1- 177-179phenyl-methylidene]-5-phenylsulphonylamino-2- indolinone phenylN-[2-(N-acetyl-N- H (Z)-3-{1-[4-(N-(2-(N-acetyl-N-methyl-amino)-ethyl)-250 methyl-amino)-ethyl]- N-propionyl-amino)-phenylamino]-1-phenyl-N-propionyl-amino methylidene}-5-phenylsulphonylamino-2-indolinonephenyl N-[2-(N-benzyl-N- H(Z)-3-{1-[4-(N-(2-(N-benzyl-N-methyl-amino)-ethyl)- 220methyl-amino)-ethyl]- N-propionyl-amino)-phenylamino]-1-phenyl-N-propionyl-amino methylidene}-5-phenylsulphonylamino-2-indolinonephenyl dimethylamino- H (Z)-3-{1-[4-(dimethylaminocarbonylmethylamino)-230-231 carbonylmethylamino phenylamino]-1-phenyl-methylidene}-5-phenylsulphonylamino-2-indolinone phenyl formylamino H(Z)-3-[1-(4-formylamino-phenylamino)-1-phenyl- 305-307methylidene]-5-phenylsulphonylamino-2-indolinone phenyl(2,6-dimethylpiperi- H (Z)-3-{1-[4-((2,6-dimethylpiperidino)-methyl)-144-145 dino)-methyl phenylamino]-1-phenyl-methylidene}-5-phenylsulphonylamino-2-indolinone phenyl N-(dimethyl- H(Z)-3-{1-[4-(N-dimethylaminomethylcarbonyl-N- 242 aminomethylcarbonyl)-methyl-amino)-phenylamino]-1-phenyl-methylidene}- N-methyl-amino5-phenylsulphonylamino-2-indolinone phenyl N-(2-dimethylamino- H(Z)-3-{1-[4-(N-(2-dimethylamino-ethyl)-N- 80 (decomp.) ethyl)-N-benzylsulphonyl-amino)-phenylamino]-1-phenyl- benzylsulphonyl-methylidene}-5-phenylsulphonylamino-2-indolinone amino phenyl2-propionylamino- H (Z)-3-{1-[4-(2-propionylamino-ethylamino)- 216ethylamino phenylamino]-1-phenyl-methylidene}-5-phenylsulphonylamino-2-indolinone phenyl N- H(Z)-3-{1-[4-(N-tert.butoxycarbonyl-N-propyl- 215 tert.butoxycarbonyl-aminomethyl)-phenylamino]-1-phenyl-methylidene)- N-propyl-5-phenylsulphonylamino-2-indolinone aminomethyl phenyl N- H(Z)-3-{1-[4-(N-tert.butoxycarbonyl-N-butyl- 207 tert.butoxycarbonyl-aminomethyl)-phenylamino]-1-phenyl-methylidene}- N-butyl-aminomethyl5-phenylsulphonylamino-2-indolinone phenyl methyl H(Z)-3-[1-(4-methylphenylamino)-1-phenyl- 192methylidene]-5-phenylsulphonylamino-2-indolinone phenylN-methyl-N-ethyl- H (Z)-3-[1-(4-(N-methyl-N-ethyl-aminomethyl)- 256aminomethyl phenylamino)-1-phenyl-methylidene]-5-phenylsulphonylamino-2-indolinone phenyl N-methyl-N-piperidi- H(Z)-3-[1-(4-(N-methyl-N-piperidinomethylcarbonyl- 274-276nomethylcarbonyl- amino)-phenylamino)-1-phenyl-methylidene]-5- aminophenylsulphonylamino-2-indolinone benzyl dimethylaminomethyl H(Z)-3-{1-[4-dimethylaminomethyl-phenylamino]-1- 242-243phenyl-methylidene}-5-benzylsulphonylamino-2- indolinone benzylpyrrolidin-1-ylmethyl H(Z)-3-{1-[4-(pyrrolidin-1-ylmethyl)-phenylamino]-1- 228phenyl-methylidene}-5-benzylsulphonylamino-2- indolinone benzyltert.butoxycarbonyl- H (Z)-3-[1-(4-tert.butoxycarbonylaminomethyl- 205aminomethyl phenylamino)-1-phenyl-methylidene]-5-benzylsulphonylamino-2-indolinone benzyl (2,6-dimethylpiperidi- H(Z)-3-{1-[4-((2,6-dimethylpiperidino)-methyl)- 140 no)-methylphenylamino]-1-phenyl-methylidene}-5- (decomp.)benzylsulphonylamino-2-indolinone 3- (2,6-dimethylpiperidi- H(Z)-3-{1-[4-((2,6-dimethylpiperidino)-methyl)- 186 methoxy- no)-methylphenylamino]-1-phenyl-methylidene}-5-(3- phenylmethoxyphenylsulphonylamino)-2-indolinone 3- pyrrolidin-1-ylmethyl H(Z)-3-{1-[4-(pyrrolidin-1-ylmethyl)-phenylamino]-1- 233 methoxy-phenyl-methylidene}-5-(3- phenylmethoxyphenylsulphonylamino)-2-indolinone 3- tert.butoxycarbonyl- H(Z)-3-[1-(4-tert.butoxycarbonylaminomethyl- 189 methoxy- aminomethylphenylamino)-1-phenyl-methylidene]-5-(3- phenylmethoxyphenylsulphonylamino)-2-indolinone 3-nitro- pyrrolidin-1-ylmethylH (Z)-3-{1-[4-(pyrrolidin-1-ylmethyl)-phenylamino)-1- 181 phenylphenyl-methylidene}-5-(3- nitrophenylsulphonylamino)-2-indolinone3-nitro- tert.butoxycarbonyl- H(Z)-3-[1-(4-tert.butoxycarbonylaminomethyl)- 238° C. phenyl aminomethylphenylamino)-1-phenyl-methylidene]-5-(3- (decomp.)nitrophenylsulphonylamino)-2-indolinone 3-nitro- (2,6-dimethylpiperidi-H (Z)-3-{1-[4-((2,6-dimethylpiperidino)-methyl)- 215 phenyl no)-methylphenylamino]-1-phenyl-methylidene}-5-(3-nitrophenylsulphonylamino)-2-indolinone 2-cyano- 4-methylpiperazino- H(Z)-3-{1-[4-(4-methylpiperazinomethyl)- 255 phenyl methylphenylamino]-1-phenyl-methylidene}-5-(2- (decomp.)cyanophenylsulphonylamino)-2-indolinone 3-amino- 4-methylpiperazino- H(Z)-3-{1-[4-(4-methylpiperazinomethyl)- 278 carbonyl- methylphenylamino]-1-phenyl-methylidene}-5-(3- (decomp.) phenylaminocarbonyl-phenyl sulphonylamino)-2-indolinone ethyl H H(Z)-3-(1-phenylamino-1-phenyl-methylidene)-5- 309ethylsulphonylamino-2-indolinone ethyl dimethylaminomethyl H(Z)-3-{1-[4-dimethylaminomethyl-phenylamino]-1- 230phenyl-methylidene}-5-ethylsulphonylamino-2- indolinone ethylN-benzyl-N-methyl- H (Z)-3-{1-[4-(N-benzyl-N-methyl-aminomethyl)- 223aminomethyl phenylamino]-1-phenyl-methylidene}-5-ethylsulphonylamino-2-indolinone ethyl 2-dimethylamino- H(Z)-3-{1-[4-(2-dimethylamino-ethyl)-phenylamino]-1- 242 ethylphenyl-methylidene}-5-ethylsulphonylamino-2- indolinone ethylN-(2-dimethylamino- H (Z)-3-{1-[4-(N-(2-dimethylamino-ethyl)-N- 240ethyl)-N-methyl- methylsulphonyl-amino)-phenylamino]-1-phenylsulphonyl-amino methylidene}-5-ethylsulphonylamino-2-indolinone ethyl ClH (Z)-3-[1-(4-chlorophenylamino)-1-phenyl- 274methylidene]-5-ethylsulphonylamino-2-indolinone ethyl nitro H(Z)-3-{1-[4-nitrophenylamino]-1-phenyl- 270methylidene}-5-ethylsulphonylamino-2-indolinone phenyl N- H(Z)-3-{1-[4-(N-tert.butoxycarbonyl-N-ethyl- 225 tert.butoxycarbonyl-aminomethyl)-phenylamino]-1-phenyl-methylidene}- N-ethyl-aminomethyl5-phenylsulphonylamino-2-indolinone ethyl 4-(3-aminopropyl)- H(Z)-3-{1-[4-(4-(3-aminopropyl)-piperidinomethyl)- 224 piperidinomethylphenylamino]-1-phenyl-methylidene}-5- ethylsulphonylamino-2-indolinoneethyl 4-(3-acetylamino- H (Z)-3-{1-[4-(4-(3-acetylamino-propyl)- 145propyl)- piperidinomethyl)-phenylamino]-1-phenyl- piperidinomethylmethylidene}-5-ethylsulphonylamino-2-indolinone pyridin-3-dimethylaminomethyl H (Z)-3-{1-[4-dimethylaminomethyl-phenylamino]-1-246-247 yl phenyl-methylidene}-5-(pyridin-3-ylsulphonylamino)-2-indolinone pyridin-3- pyrrolidin-1-ylmethyl H(Z)-3-{1-[4-(pyrrolidin-1-ylmethyl)-phenylamino]-1- 235-236 ylphenyl-methylidene}-5-(pyridin-3-ylsulphonylamino)- 2-indolinonepyridin-3- N-acetyl-N-methyl- H (Z)-3-{1-[4-(N-acetyl-N-methyl-amino)-240-241 yl amino phenylamino]-1-phenyl-methylidene}-5-(pyridin-3-ylsulphonylamino)-2-indolinone pyridin-3- N-methyl-N- H(Z)-3-{1-[4-(N-methyl-N-methylsulphonyl-amino)- 286-287 ylmethylsulphonyl- phenylamino]-1-phenyl-methylidene}-5-(pyridin-3- aminoyisulphonylamino)-2-indolinone pyridin-3- N-(2-dimethylamino- H(Z)-3-{1-[4-(N-(2-dimethylamino-ethyl)-N- 249-250 yl ethyl)-N-methylsulphonyl-amino)-phenyl amino]-1-phenyl- methylsulphonyl-methylidene}-5-(pyridin-3-ylsulphonylamino)-2- amino indolinonepyridin-3- 1H-imidazol-2-yl H(Z)-3-{1-[4-(1H-imidazol-2-yl)-phenylamino]-1- 222-223 ylphenyl-methylidene}-5-(pyridin-3-ylsulphonylamino)- 2-indolinonepyridin-3- 1-methyl-1H- H (Z)-3-{1-[4-(1-methyl-1H-imidazol-2-yl)-230-231 yl imidazol-2-ylphenylamino]-1-phenyl-methylidenel-5-(pyridin-3-ylsulphonylamino)-2-indolinone pyridin-3- dimethylamino- H(Z)-3-{1-[4-dimethylaminocarbonyl-phenylamino]-1- 171-172 yl carbonylphenyl-methylidene}-5-(pyridin-3-ylsulphonylamino)- 2-indolinonepyridin-3- 4-methyl- H (Z)-3-{1-[4-(4-methylpiperazinomethyl)- 258-259yl piperazinomethyl phenylamino]-1-phenyl-methylidene}-5-(pyridin-3-ylsulphonylamino)-2-indolinone pyridin-3- pyrrolidin-1- H(Z)-3-{1-[4-(pyrrolidin-1-ylcarbonyl)-phenylamino]-1- 284-285 ylylcarbonyl phenyl-methylidene}-5-(pyridin-3-ylsulphonylamino)-2-indolinone pyridin-3- N-(2-dimethylamino- Cl(Z)-3-{1-[3-chloro-4-(N-(2-dimethylamino-ethyl)-N- 261-262 yl ethyl)-N-methylsulphonyl-amino)-phenylamino]-1-phenyl- methylsulphonyl-methylidene}-5-(pyridin-3-ylsulphonylamino)-2- amino indolinonepyridin-3- N-(2-dimethylamino- NH₂(Z)-3-{1-[3-amino-4-(N-(2-dimethylamino-ethyl)-N- 272-273 yl ethyl)-N-methylsulphonyl-amino)-phenylamino]-1-phenyl- methylsulphonyl-methylidene}-5-(pyridin-3-ylsulphonylamino)-2- amino indolinonepyridin-2- 4-methyl- H (Z)-3-{1-[4-(4-methylpiperazinomethyl)- 210 ylpiperazinomethyl phenylamino]-1-phenyl-methylidene}-5-(pyridin-2-(decomp.) ylsulphonylamino)-2-indolinone pyridin-2- N-acetyl-N-[2-(N- H(Z)-3-{1-[4-(N-acetyl-N-(2-(N-benzyl-N-methyl- 232-235 ylbenzyl-N-methyl- amino)-ethyl)-amino)-phenylamino]-1-phenyl-amino)-ethyl]-amino methylidene}-5-(pyridin-2-ylsulphonylamino)-2-indolinone pyridin-2- N-(3-dimethylamino- H(Z)-3-{1-[4-(N-(3-dimethylamino-propyl)-N- 217-219 ylpropyl)-N-propionyl- propionyl-amino)-phenylamino]-1-phenyl- aminomethylidene}-5-(pyridin-2-ylsulphonylamino)-2- indolinone pyridin-2-N-(3-dimethylamino- H (Z)-3-{1-[4-(N-(3-dimethylamino-propyl)-N- 258-260yl propyl)-N- methylsulphonyl-amino)-phenylamino]-1-phenyl-methylsulphonyl- methylidene}-5-(pyridin-2-ylsulphonylamino)-2- aminoindolinone pyridin-2- N-(3-dimethylamino- H(Z)-3-{1-[4-(N-(3-dimethylamino-propyl)-N- 256-257 yl propyl)-N-propylsulphonyl-amino)-phenylamino]-1-phenyl- propylsulphonyl-methylidene}-5-(pyridin-2-ylsulphonylamino)-2- amino indolinonepyridin-2- N-(2-dimethylamino- H(Z)-3-{1-[4-(N-(2-dimethylamino-ethyl)-N- 269-271 yl ethyl) -N-methylsulphonyl-amino)-phenylamino]-1-phenyl- methylsulphonyl-methylidene}-5-(pyridin-2-ylsulphonylamino)-2- amino] indolinonepyridin-2- N-piperidinomethyl- H(Z)-3-{1-[4-(N-piperidinomethylcarbonyl-N-methyl- 236-237 ylcarbonyl-N-methyl- amino)-phenylamino]-1-phenyl-methylidene}-5- amino(pyridin-2-ylsulphonylamino)-2-indolinone

EXAMPLE 98

[0499](Z)-3-[1-(4-piperidinomethyl-phenylamino)-1-phenyl-methylidene]-5-methylsulphonylamino-2-indolinone

[0500] a.1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone

[0501] 0.2 g (0.9 mmol) of 1-acetyl-5-nitro-2-indolinone and 0.6 g (2.7mmol) of triethyl orthobenzoate are heated to 100° C. in 2 ml of aceticacid anhydride for 1.5 hours. After cooling the mixture is combined withether and the precipitate formed is suction filtered.

[0502] Yield: 0.2 g (66% of theory),

[0503] Melting point: 244-250° C.

[0504] R_(f) value: 0.7 (silica gel; ethyl acetate/cyclohexane=3:2)

[0505] b.(Z)-1-acetyl-3-[1-(4-piperidinomethyl-phenylamino)-1-phenyl-methylidene]-5-nitro-2-indolinone

[0506] 3 g (8.5 mmol) of1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and 1.9g (10 mmol) of 4-piperidinomethyl-aniline are heated to 90° C. in 30 mlof DMF for 3.5 hours. After cooling to ambient temperature the reactionsolution is poured onto ice water and extracted with ethyl acetate. Thecombined organic extracts are dried and evaporated down. The residue istriturated with ether and suction filtered.

[0507] Yield: 3.5 g (82% of theory),

[0508] R_(f) value: 0.6 (silica gel;dichloromethane/methanol/ammonia=9:1:0.1)

[0509] Melting point: 165° C.

[0510] c.(Z)-1-acetyl-3-[1-(4-piperidinomethyl-phenylamino)-1-phenyl-methylidene]-5-amino-2-indolinone

[0511] Prepared analogously to Example VIIb from(Z)-1-acetyl-3-[1-(4-piperidinomethyl-phenylamino)-1-phenyl-methylidene]-5-nitro-2-indolinoneby catalytic reduction over Raney nickel in dichloromethane/methanol(1:1).

[0512] Yield: 99% of theory,

[0513] R_(f) value: 0.5 (silica gel;dichloromethane/methanol/ammonia=9:1:0.1)

[0514] Melting point: 278-281° C.

[0515] C₂₉H₃₀N₄O₂ (466.59)

[0516] Mass spectrum: (M+H)⁺=467

[0517] d.(Z)-3-[1-(4-piperidinomethyl-phenylamino)-1-phenyl-methylidene]-5-methylsulphonylamino-2-indolinone

[0518] 466 mg (1 mmol) of(Z)-1-acetyl-3-[1-(4-piperidinomethyl-phenylamino)-1-phenyl-methylidene]-5-amino-2-indolinoneare suspended in 15 ml of pyridine, combined with 0.2 ml (2.3 mmol) ofmethanesulphonic acid chloride and stirred for 1.5 hours. Then 6 ml of 1N sodium hydroxide solution are added. After 1 hour 1 ml of piperidineis added and the mixture is stirred overnight. The reaction solution ispoured onto water and the precipitate formed is suction filtered. Theresidue is stirred with ether, suction filtered and dried.

[0519] Yield: 290 mg (58% of theory),

[0520] R_(f) value: 0.4 (silica gel;dichloromethane/methanol/ammonia=9:1:0.1)

[0521] Melting point: 266° C.

[0522] C₂₈H₃₀N₄O₃S (502.64)

[0523] Mass spectrum: (M+H)⁺=503 Calc.: C 66.91 H 6.02 N 11.15 Found: C66.49 H 6.06 N 11.01

EXAMPLES 99 to 151

[0524] Using the intermediate products prepared in Examples I to XIII,the compounds of formula IB of Examples 99 to 151 listed in Table II areprepared analogously to Example 98.

[0525] Hydrochlorides or dihydrochlorides are obtained according to thefollowing general working method: The starting compound is dissolved indichloromethane and combined with ether/HCl. The precipitate formed issuction filtered and dried. TABLE II (IB),

Melting point Example R₂ R₇ chemical name (° C.) ethyl piperidinomethyl(Z)-3-{1-[4-(piperidinomethyl)-phenylamino]-1-phenyl- 235methylidene}-5-ethylsulphonylamino-2-indolinone ethyl methoxy(Z)-3-[1-(4-methoxyphenylamino)-1-phenyl-methylidene]-5-ethyl- 283sulphonylamino-2-indolinone isopropyl piperidinomethyl(Z)-3-{1-[4-(piperidinomethyl)-phenylamino]-1-phenyl- 205methylidene}-5-isopropylsulphonylamino-2-indolinone 4- piperidinomethyl(Z)-3-{1-[4-(piperidinomethyl)-phenylamino]-1-phenyl- 251-253chlorophenyl methylidene}-5-(4-chlorophenylsulphonylamino)-2-indolinone3- piperidinomethyl(Z)-3-{1-[4-(piperidinomethyl)-phenylamino]-1-phenyl- 275-277chlorophenyl methylidene}-5-(3-chlorophenylsulphonylamino)-2-indolinonenaphthalin-1- piperidinomethyl(Z)-3-{1-[4-(piperidinomethyl)-phenylamino]-1-phenyl- 236-237 ylmethylidene}-5-(naphthalin-1-ylsulphonylamino)-2-indolinone 4-piperidinomethyl (Z)-3-{1-[4-(piperidinomethyl)-phenylamino]-1-phenyl-267-269 methylphenylmethylidene}-5-(4-methylphenylsulphonylamino)-2-indolinone 3-piperidinomethyl (Z)-3-{1-[4-(piperidinomethyl)-phenylamino]-1-phenyl-269-271 methylphenyl methylidene}-5-(3-methylphenylsulphonylamino)-2-indolinone 3- piperidinomethyl(Z)-3-{1-[4-(piperidinomethyl)-phenylamino]-1-phenyl- 241-245methoxyphen methylidene)-5-(3-methoxyphenylsulphonylamino)-2-indolinoneyl 2- piperidinomethyl(Z)-3-{1-[4-(piperidinomethyl)-phenylamino]-1-phenyl- 275 chlorophenylmethylidene}-5-(2-chlorophenylsulphonylamino)-2-indolinone 2-nitrophenylpiperidinomethyl (Z)-3-{1-[4-(piperidinomethyl)-phenylamino]-1-phenyl-140 methylidene}-5-(2-nitrophenylsulphonylamino)-2-indolinone 3-piperidinomethyl (Z)-3-{1-[4-(piperidinomethyl)-phenylamino]-1-phenyl-248 cyanophenylmethylidene}-5-(3-cyanophenylsulphonylamino)-2-indolinone 3,5-piperidinomethyl (Z)-3-{1-[4-(piperidinomethy1)-phenylamino]-1-phenyl-240 dimethylisoxamethylidene}-5-(3,5-dimethylisoxazol-4-ylsulphonylamino)-2- zol-4-ylindolinone E-2- piperidinomethyl(Z)-3-{1-[4-(piperidinomethyl)-phenylamino]-1-phenyl- 248 phenylethenylmethylidene}-5-((E)-2-phenylethenylsulphonylamino)-2-indolinone1-methyl-1H- piperidinomethyl(Z)-3-{1-[4-(piperidinomethyl)-phenylamino]-1-phenyl- 230 imidazol-4-ylmethylidene}-5-(1-methyl-1H-imidazol-4-ylsulphonylamino)-2-indolinone-dihydrochloride cyclopropyl piperidinomethyl(Z)-3-{1-[4-(piperidinomethyl)-phenylamino]-1-phenyl- 231methylidene}-5-cyclopropylsulphonylamino-2-indolinone 2-piperidinomethyl (Z)-3-{1-[4-(piperidinomethyl)-phenylamino]-1-phenyl-239 cyanophenylmethylidene}-5-(2-cyanophenylsulphonylamino)-2-indolinone pyridin-2-ylpiperidinomethyl (Z)-3-{1-[4-(piperidinomethyl)-phenylamino]-1-phenyl-263 methylidene}-5-(pyridin-2-ylsulphonylamino)-2-indolinone phenylpiperidinomethyl (Z)-3-{1-[4-(piperidinomethyl)-phenylamino]-1-phenyl-262 methylidene}-5-phenylsulphonylamino-2-indolinone benzylpiperidinomethyl (Z)-3-{1-[4-(piperidinomethyl)-phenylamino]-1-phenyl-254 methylidene}-5-benzylsulphonylamino-2-indolinone propylpiperidinomethyl (Z)-3-{1-[4-(piperidinomethy1)-pheny1amino]-1-phenyl-188 methylidene}-5-propylsulphonylamino-2-indolinone benzylN-(2-dimethylami-(Z)-3-{1-[4-(N-(2-dimethylamino-ethyl)-N-methylsulphonyl- 163-164no-ethyl)-N-methyl- amino)-phenylamino]-1-phenyl-methylidene}-5-sulphonyl-amino benzylsulphonylamino-2-indolinone isopropyl2-dimethylamino-(Z)-3-{1-[4-(2-dimethylamino-ethyl)-phenylamino]-1-phenyl- 220 ethylmethylidene}-5-isopropylsulphonylamino-2-indolinone propyl2-dimethylamino-(Z)-3-{1-[4-(2-dimethylamino-ethyl)-phenylamino]-1-phenyl- 239-240 ethylmethylidene}-5-propylsulphonylamino-2-indolinone propylN-benzyl-N-methyl-(Z)-3-{1-[4-(N-benzyl-N-methyl-aminomethyl)-phenylamino]-1- 195-197aminomethyl phenyl-methylidene}-5-propylsulphonylamino-2-indolinonemethyl N-benzyl-N-methyl-(Z)-3-{1-[4-(N-benzyl-N-methyl-aminomethyl)-phenylamino]-1- 241-242aminomethyl phenyl-methylidene}-5-methylsulphonylamino-2-indolinonephenyl N-benzyl-N-methyl-(Z)-3-{1-[4-(N-benzyl-N-methyl-aminomethyl)-phenylamino]-1- 148-150aminomethyl phenyl-methylidene}-5-phenylsulphonylamino-2-indolinonebenzyl N-benzyl-N-methyl-(Z)-3-{1-[4-(N-benzyl-N-methyl-aminomethyl)-phenylamino]-1- 200-204aminomethyl phenyl-methylidene}-5-benzylsulphonylamino-2-indolinonebenzyl 2-dimethylamino-(Z)-3-{1-[4-(2-dimethylamino-ethyl)-phenylamino]-1-phenyl- 260-262 ethylmethylidene}-5-benzylsulphonylamino-2-indolinone-hydrochloridepyridin-3-yl piperidinomethyl(Z)-3-{1-[4-(piperidinomethyl)-phenylamino]-1-phenyl- 236methylidene}-5-(pyridin-3-ylphenylsulphonylamino)-2-indolinone3-nitrophenyl dimethylamino-(Z)-3-{1-[4-(dimethylaminomethyl)-phenylamino]-1-phenyl- 246-247 methylmethylidene}-5-(3-nitrophenylsulphonylamino)-2-indolinone 3-methoxy-dimethylamino- (Z)-3-{1-[4-(dimethylaminomethyl)-phenylamino]-1-phenyl-259-260 phenyl methylmethylidene}-5-(3-methoxyphenylsulphonylamino)-2-indolinone3-nitrophenyl dimethylamino-(Z)-3-{1-[4-(N-methyl-N-acetyl-amino)-phenylamino]-1-phenyl- 298-300methyl amino methylidene}-5-(3-nitrophenylsulphonylamino)-2-indolinone2-nitrophenyl N-methyl-N-acetyl-(Z)-3-{1-[4-(N-methyl-N-acetyl-amino)-phenylamino]-1-phenyl- 295-297amino methylidene}-5-(2-nitrophenylsulphonylamino)-2-indolinone 3-N-methyl-N-acetyl-(Z)-3-{1-[4-(N-methyl-N-acetyl-amino)-phenylamino]-1-phenyl- 330-332cyanophenyl amino methylidene}-5-(3-cyanophenylsulphonylamino)-2-indolinone 3-nitrophenyl 4-methyl-(Z)-3-{1-[4-(4-methylpiperazinomethyl)-phenylamino]-1-phenyl- 166-167piperazinomethylmethylidene}-5-(3-nitrophenylsulphonylamino)-2-indolinone pyridin-2-ylpyrrolidin-1- (Z)-3-{1-[4-(pyrrolidin-1-ylmethyl)-phenylamino]-1-phenyl-261 ylmethyl methylidene}-5-(pyridin-2-ylsulphonylamino)-2-indolinonecyclopropyl pyrrolidin-1-(Z)-3-{1-[4-(pyrrolidin-1-ylmethyl)-phenylamino]-1-phenyl- 256 ylmethylmethylidene}-5-cyclopropylsulphonylamino-2-indolinone propylpyrrolidin-1- (Z)-3-{1-[4-(pyrrolidin-1-ylmethyl)-phenylamino]-1-phenyl-247 ylmethyl methylidene}-5-propylsulphonylamino-2-indolinone ethylpyrrolidin-1- (Z)-3-{1-[4-(pyrrolidin-1-ylmethyl)-phenylamino]-1-phenyl-245 ylmethyl methylidene}-5-ethylsulphonylamino-2-indolinone methylpyrrolidin-1- (Z)-3-{1-[4-(pyrrolidin-1-ylmethyl)-phenylamino]-1-phenyl-248 ylmethyl methylidene}-5-methylsulphonylamino-2-indolinone 2-pyrrolidin-1- (Z)-3-{1-[4-(pyrrolidin-1-ylmethyl)-phenylamino]-1-phenyl-247 fluorophenyl ylmethylmethylidene}-5-(2-fluorophenylsulphonylamino)-2-indolinone 4-pyrrolidin-1- (Z)-3-{1-[4-(pyrrolidin-1-ylmethyl)-phenylamino]-1-phenyl-244 fluorophenyl ylmethylmethylidene}-5-(4-fluorophenylsulphonylamino)-2-indolinone 3-pyrrolidin-1- (Z)-3-{1-[4-(pyrrolidin-1-ylmethyl)-phenylamino]-1-phenyl-257 fluorophenyl ylmethylmethylidene}-5-(3-fluorophenylsulphonylamino)-2-indolinone 2-nitrophenylpyrrolidin-1- (Z)-3-{1-[4-(pyrrolidin-1-ylmethyl)-phenylamino]-1-phenyl-185 ylmethyl methylidene}-5-(2-nitrophenylsulphonylamino)-2-indolinone3- pyrrolidin-1-(Z)-3-{1-[4-(pyrrolidin-1-ylmethyl)-phenylamino]-1-phenyl- 249cyanophenyl ylmethylmethylidene}-5-(3-cyanophenylsulphonylamino)-2-indolinone 2-pyrrolidin-1- (Z)-3-{1-[4-(pyrrolidin-1-ylmethyl)-phenylamino]-1-phenyl-232 cyanophenyl ylmethylmethylidene}-5-(2-cyanophenylsulphonylamino)-2-indolinone

EXAMPLE 152

[0526](Z)-3-[1-(4-ethoxycarbonylmethyl-phenylamino)-1-phenyl-methylidene]-5-phenylsulphonylamino-2-indolinone

[0527] a.3-(1-ethoxy-1-phenyl-methylidene)-5-phenylsulphonylamino-2-indolinone

[0528] 8 ml of 4 N sodium hydroxide solution are added to a solution of4.0 g (8 mmol) of1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5-(N-acetyl-N-phenylsulphonyl-amino)-2-indolinone(Example Ie) in a mixture of 20 ml of dichloromethane and 20 ml ofethanol and the resulting mixture is stirred for 20 minutes at ambienttemperature. It is then evaporated down to about. 10 ml and 150 ml ofwater are added. The pH is adjusted to 8-9 with 1 N hydrochloric acid.The precipitate formed is suction filtered, washed with water,isopropanol and ether, then dried in vacuo.

[0529] Yield: 6.6 g (82% of theory),

[0530] Melting point: 292-294° C.

[0531] R_(f) value: 0.4 (silica gel;dichloromethane/methanol/NH₄OH=9:1:0.1)

[0532] C₂₃H₂₀N₂O₄S (420.49)

[0533] Mass spectrum: (M+H)⁺=421, (M−H)⁻=419

[0534] b.(Z)-3-[1-(4-ethoxycarbonylmethyl-phenylamino)-1-phenyl-methylidene]-5-phenylsulphonylamino-2-indolinone

[0535] 0.84 g (2 mmol) of3-(1-ethoxy-1-phenyl-methylidene)-5-phenylsulphonylamino-2-indolinoneand 0.39 g (2.2 mmol) of 4-ethoxycarbonylmethyl-aniline are dissolved in10 ml of DMF. The mixture is heated to 140° C. for 5 hours. Then wateris added while the mixture is cooled with ice and stirred for 1 hour atambient temperature. The precipitate formed is suction filtered, washedwith water, a little isopropanol and ether, then dried in vacuo.

[0536] Yield: 0.95 g (86% of theory),

[0537] Melting point: 248-249° C.

[0538] C₃₁H₂₇N₃O₅S (553.64)

[0539] Mass spectrum: M⁺=553, (M−H)⁻=552

EXAMPLE 153

[0540](Z)-3-[1-(4-carboxymethyl-phenylamino)-1-phenyl-methylidene]-5-phenylsulphonylamino-2-indolinone

[0541] 720 mg (1.3 mmol) of(Z)-3-[1-(4-ethoxycarbonylmethyl-phenylamino)-1-phenyl-methylidene]-5-phenylsulphonylamino-2-indolinoneare dissolved in a mixture of 20 ml of methanol and 20 ml ofdichloromethane. 4 ml of 1 N sodium hydroxide solution are added and themixture is stirred for 18 hours at ambient temperature and for another 1hour at 40° C. The reaction solution is evaporated down to half thevolume and the pH is adjusted to 4-5 with 1 N hydrochloric acid. Theprecipitate formed is suction filtered, washed with water, a littleisopropanol and ether.

[0542] Yield: 620 mg (91% of theory),

[0543] Melting point: 305-306° C.

[0544] C₂₉H₂₃N₃O₅S (525.59)

[0545] Mass spectrum: (M−H)⁻=524

EXAMPLE 154

[0546](Z)-3-{1-[4-(benzylaminocarbonylmethyl)-phenylamino]-1-phenyl-methylidene}-5-phenylsulphonylamino-2-indolinone

[0547] A solution of 315 mg (0.6 mmol) of(Z)-3-[1-(4-carboxymethyl-phenylamino)-1-phenyl-methylidene]-5-phenylsulphonylamino-2-indolinone,85 mg (0.8 mmol) of benzylamine, 212 mg (0.66 mmol) of TBTU and 1 ml ofN-ethyl-N,N-diisopropyl-amine in 5 ml of DMF is stirred for 3 hours atambient temperature. Then 50 ml of water are added. The yellowprecipitate formed is suction filtered, washed with water, a littleisopropanol and ether, then dried in vacuo.

[0548] Yield: 0.3 mg (81% of theory),

[0549] Melting point: 219-220° C.

[0550] C₃₆H₃₀N₄O₄S (614.73)

[0551] Mass spectrum: (M+Na)⁺=637, (M−H)⁻=613

EXAMPLE 155

[0552](Z)-3-{1-[4-(N-(aminocarbonylmethyl)-N-methylsulphonyl-amino)-phenylamino]-1-phenyl-methylidene}-5-phenylsulphonylamino-2-indolinone

[0553] A solution of 250 mg (0.4 mmol) of(Z)-3-[1-(4-(N-carboxymethyl-N-methylsulphonyl-amino)-phenylamino)-1-phenyl-methylidene]-5-phenylsulphonylamino-2-indolinoneand 82 mg (0.4 mmol) of CDI in 5 ml of DMF is stirred for 1 hour at 50°C. 1 ml of condensed ammonia is added and the mixture is stirred for 5hours at ambient temperature. Then water is added. The yellowprecipitate is suction filtered, washed with water, a little isopropanoland ether, then dried in vacuo.

[0554] Yield: 190 mg (76% of theory)

[0555] Melting point: 216-217° C.

[0556] C₃₀H₂₇N₅O₆S₂ (617.71)

[0557] Mass spectrum: (M+Na)⁺=640, (M−H)⁻=616

EXAMPLES 156 to 170

[0558] Using the intermediate products prepared in Examples I to XIII,the compounds of formula IB of Examples 156 to 170 listed in Table IIIare prepared analogously to Examples 152 to 155. TABLE III (IB)

Melting point Example R₂ R₇ chemical name (° C.) phenyl methoxycarbonyl(Z)-3-[1-(4-methoxycarbonyl-phenylamino)-1-phenyl- 304-305methylidene]-5-phenylsulphonylamino-2-indolinone phenyl carboxy(Z)-3-[1-(4-carboxyphenylamino)-1-phenyl-methylidene]-5- 312-313phenylsulphonylamino-2-indolinone phenyl benzylaminocarbonyl(Z)-3-{1-[4-(benzylaminocarbonyl)-phenylamino]-1-phenyl- 269-270methylidene}-5-phenylsulphonylamino-2-indolinone methyl methoxycarbonyl(Z)-3-[1-(4-methoxycarbonyl-phenylamino)-1-phenyl- >270methylidene]-5-methylsulphonylamino-2-indolinone methyl carboxy(Z)-3-[1-(4-carboxyphenylamino)-1-phenyl-methylidene]-5- >270methylsulphonylamino-2-indolinone phenyl N-carboxymethyl-N-acetyl-(Z)-3-{1-[4-(N-carboxymethyl-N-acetyl-amino)-phenylamino]- 190-191 amino1-phenyl-methylidene}-5-phenylsulphonylamino-2-indolinone phenylN-aminocarbonylmethyl-N-(Z)-3-{1-[4-(N-(aminocarbonylmethyl)-N-acetyl-amino)- 150 (decomp.)acetyl-amino phenylamino]-1-phenyl-methylidene}-5-phenylsulphonylamino-2-indolinone phenyl N-methylaminocarbonyl-(Z)-3-{1-[4-(N-methylaminocarbonylmethyl-N-acetyl-amino)- 150 (decomp.)methyl-N-acetyl-aminophenylamino]-1-phenyl-methylidene}-5-phenylsuiphonylamino- 2-indolinonephenyl N-dimethylaminocarbonyl-(Z)-3-{1-[4-(N-dimethylaminocarbonylmethyl-N-acetyl-amino)- 150(decomp.) methyl)-N-acetyl-amino)phenylamino]-1-phenyl-methylidene}-5-phenylsulphonylamino- 2-indolinonephenyl N-carboxymethyl-N-(Z)-3-{1-[4-(N-carboxymethyl-N-ethylsulphonyl-amino)- 231-235ethylsulphonyl-aminophenylamino]-1-phenyl-methylidene}-5-phenylsulphonylamino- 2-indolinonephenyl N-[N-(2-dimethylamino-(Z)-3-{1-[4-(N-(N-(2-dimethylamino-ethyl)-N-methyl- 147-151ethyl)-N-methyl-amino-aminocarbonylmethyl)-N-ethylsulphonyl-amino)-phenylamino]-carbonylmethyl]-N-1-phenyl-methylidene}-5-phenylsulphonylamino-2-indolinoneethylsulphonyl-amino phenyl N-[(2-dimethylamino-ethyl)-(Z)-3-{1-[4-(N-((2-dimethylamino-ethyl)- 142-147 aminocarbonylmethyl]-N-aminocarbonylmethyl)-N-ethylsulphonyl-amino)-phenylamino]-ethylsulphonyl-amino1-phenyl-methylidene}-5-phenylsulphonylamino-2-indolinone phenylN-carboxylmethyl-N-(Z)-3-{1-{4-(N-carboxylmethyl-N-methylsulphonyl-amino)- 215-216methylsulphonyl-aminophenylamino]-1-phenyl-methylidene}-5-phenylsulphonylamino- 2-indolinonephenyl N-methylaminocarbonyl-(Z)-3-{1-[4-(N-methylaminocarbonylmethyl-N- 150 (decomp.)methyl-N-methylsulphonyl-methylsulphonyl-amino)-phenylamino]-1-phenyl-methylidene} amino5-phenylsulphonylamino-2-indolinone phenyl N-dimethylamino-(Z)-3-{1-[4-(N-dimethylaminocarbonylmethyl-N- 150 (decomp.)carbonylmethyl-N-methylsulphonyl-amino)-phenylamino]-1-phenyl-methylidene}-methylsulphonyl-amino 5-phenylsulphonylamino-2-indolinone

EXAMPLES 171 to 206

[0559] The compounds of formula IB of Examples 171 to 206 listed in thefollowing Table IV are obtained from compounds of the abovementionedExamples 1 to 170 by the following general methods A to E or analogouslyto Example 1 or 210:

[0560] A: Cleaving of Tert.butoxycarbonyl:

[0561] 0.6 mmol of the starting compound are dissolved in 5 ml ofdichloromethane. 10 ml of ethyl acetate/HCl are added and the mixture isstirred for 2 hours at ambient temperature. Then a basic pH is obtainedby the addition of sodium hydroxide solution. The organic phase iswashed with water, dried over sodium sulphate and the solvent iseliminated in vacuo. In order to prepare hydrochlorides the addition ofsodium hydroxide solution is omitted. In order to preparehydrotrifluoroacetate, trifluoroacetic acid is added to the solution ofthe starting compound.

[0562] B: Cleaving of Benzyl:

[0563] 1.5 mmol of the starting compound are dissolved in 20 ml ofdichloromethane/methanol (1:1). 100 mg of palladium/charcoal (10%) and1.5 ml of 1 N hydrochloric acid are added and the mixture is thenhydrogenated in a hydrogen atmosphere at 50 psi. The catalyst is suctionfiltered and the filtrate is evaporated to dryness. The residue ischromatographed on silica gel (dichloromethane/methanol/NH₄OH, 9:1:0.1).

[0564] C: Hydrogenation of Cyano to CH₂NH₂:

[0565] 0.5 mmol of the starting compound are dissolved in 20 ml ofmethanolic ammonia solution and combined with Raney nickel. The mixtureis hydrogenated in a hydrogen atmosphere of 50 psi, then the catalyst issuction filtered and the solvent is eliminated in vacuo. The residue ischromatographed on silica gel (dichloromethane/methanol/NH₄OH, 9:1:0.1).

[0566] D: Hydrogenation of Nitro to Amino:

[0567] 0.2 mmol of the starting compound are dissolved in 20 ml of ethylacetate/methanol (1:1). Then the mixture is hydrogenated analogously toMethod C over Raney nickel. The residue is optionally chromatographed onsilica gel (dichloromethane/methanol/NH₄OH, 9:1:0.1). TABLE IV (IB)

Melting point Example method R₂ R₆ R₇ chemical name (° C.) A phenyl Hamino (Z)-3-[1-(4-aminophenylamino)-1-phenyl-methylidene]-5- 220-223phenylsulphonylamino-2-indolinone A phenyl H piperazino-(Z)-3-[1-(4-piperazinomethyl-phenylamino)-1-phenyl- 380 methylmethylidene]-5-phenylsulphonylamino-2-indolinone (decomp.) A 3-methoxy-H aminomethyl (Z)-3-[1-(4-aminomethyl-phenylamino)-1-phenyl- 200 phenylmethylidene]-5-(3-methoxyphenylsulphonylamino)-2- (decomp.)indolinone-hydrochloride A benzyl H aminomethyl(Z)-3-[1-(4-aminomethyl-phenylamino)-1-phenyl- 200methylidene]-5-benzylsulphonylamino)-2-indolinone- (decomp.)hydrochloride A 3-nitrophenyl H aminomethyl(Z)-3-[1-(4-aminomethyl-phenylamino)-1-phenyl- 215methylidene]-5-(3-nitrophenylsulphonylamino)-2- (decomp.)indolinone-hydrochloride A phenyl H ethylamino-(Z)-3-[1-(4-ethylaminomethyl-phenylamino)-1-phenyl- 230 methylmethylidene]-5-phenylsulphonylamino-2-indolinone- hydrotrifluoroacetateA phenyl H propylamino-(Z)-3-[1-(4-propylaminomethyl-phenylamino)-1-phenyl- 238 methylmethylidene]-5-phenylsulphonylamino-2-indolinone- hydrotrifluoroacetateA phenyl H butylamino-(Z)-3-[1-(4-butylaminomethyl-phenylamino)-1-phenyl- 260 methylmethylidene]-5-phenylsulphonylamino-2-indolinone- hydrotrifluoroacetateB phenyl H N-(2- (Z)-3-{1-[4-(N-(2-methylamino-ethyl)-N-acetyl-amino)-180 methylamino- phenylamino]-1-phenyl-methylidene}-5- (decomp.)ethyl)-N- phenylsulphonylamino-2-indolinone acetyl-amino B phenyl HN-(2- (Z)-3-{1-[4-(N-(2-methylamino-ethyl)-N-propionyl- 214methylamino-amino)-phenylamino]-1-phenyl-methylidene}-5-ethyl)-N-phenylsulphonylamino-2-indolinone propionyl- amino C 3- Hpiperidinomethyl (Z)-3-[1-(4-piperidinomethyl-phenylamino]-1-phenyl- 237aminomethyl methylidene]-5-(3-aminomethyl-phenylsulphonylamino)-2-phenyl indolinone C phenyl H aminomethyl(Z)-3-[1-(4-aminomethyl-phenylamino)-1-phenyl- 230-232methylidene]-5-phenylsulphonylamino-2-indolinone C 2- H piperidinomethyl(Z)-3-[1-(4-piperidinomethyl-phenylamino]-1-phenyl- 237 aminomethylmethylidene]-5-(2-aminomethyl-phenylsulphonylamino)-2- phenyl indolinoneC 3- H N-methyl-N- (Z)-3-{1-[4-(N-methyl-N-acetyl-amino)-phenylamino]-1-277-279 aminomethyl acetyl-aminophenyl-methylidene}-5-(3-aminomethyl-phenylsulphonyl- phenylamino)-2-indolinone C 3- H pyrrolidin-1-(Z)-3-[1-(4-pyrrolidin-1-ylmethyl-phenylamino]-1-phenyl- 261 aminomethylylmethyl methylidene]-5-(3-aminomethyl-phenylsulphonylamino)-2- phenylindolinone D 4- H piperidinomethyl(Z)-3-[1-(4-piperidinomethyl-phenylamino)-1-phenyl- 279 aminophenylmethylidene]-5-(4-aminophenylsulphonylamino)-2- indolinone D 3- Hpiperidinomethyl (Z)-3-[1-(4-piperidinomethyl-phenylamino)-1-phenyl- 240aminophenyl methylidene]-5-(3-aminophenylsulphonylamino)-2- indolinone D2- H piperidinomethyl(Z)-3-[1-(4-piperidinomethyl-phenylamino]-1-phenyl- 220 aminophenylmethylidene]-5-(2-aminophenylsulphonylamino)-2- (decomp.)indolinone-hydrochloride D 3- H dimethylamino(Z)-3-[1-(4-dimethylaminomethyl-phenylamino)-1-phenyl- 250 aminophenylmethyl methylidene]-5-(3-aminophenylsulphonylamino)-2- (decomp.)indolinone D 3- H N-methyl-N-(Z)-3-{1-[4-(N-methyl-N-acetyl-amino)-phenylamino]-1- 207-209aminophenyl acetyl-aminophenyl-methylidene}-5-(3-aminophenylsulphonylamino)-2- indolinone D 2- HN-methyl-N- (Z)-3-{1-[4-(N-methyl-N-acetyl-amino)-phenylamino]-1-295-298 aminophenyl acetyl-aminophenyl-methylidene}-5-(2-aminophenylsulphonylamino)-2- indolinone D 3- Hpyrrolidin-1- (Z)-3-{1-[4-(pyrrolidin-1-ylmethyl)-phenylamino)-1- 242aminophenyl ylmethylphenyl-methylidene}-5-(3-aminophenylsulphonylamino)-2- indolinone D 3- H(2,6- (Z)-3-{1-[4-((2,6-dimethylpiperidino)-methyl)- 150 aminophenyldimethylpiperidino)-phenylamino]-1-phenyl-methylidene}-5-(3-aminophenyl- (decomp.) methylsulphonylamino)-2-indolinone D 3- H aminomethyl(Z)-3-[1-(4-aminomethyl-phenylamino)-1-phenyl- 257 aminophenylmethylidene]-5-(3-aminophenylsulphonylamino)-2- indolinone D 3- H 4-(Z)-3-{1-[4-(4-methylpiperazinomethyl)-phenylamino]-1- 217-218aminophenyl methylpiperazino-phenyl-methylidene}-5-(3-aminophenylsulphonylamino)-2- methyl indolinoneD 2- H pyrrolidin-1- (Z)-3-{1-[4-(pyrrolidin-l-ylmethyl)-phenylamino)-1-260 aminophenyl ylmethylphenyl-methylidene}-5-(2-aminophenylsulphonylamino)-2- indolinone Ex. 1methyl H acetylamino (Z)-3-{1-[4-acetylamino-phenylamino)-1-phenyl-299-303 methylidene}-5-methylsulphonylamino-2-indolinone Ex. 1 ethyl H2- (Z)-3-{1-[4-(2-dimethylamino-acetylamino)-phenylamino]- 238-241dimethylamino- 1-phenyl-methylidene}-5-ethylsulphonylamino-2-acetylamino indolinone Ex. 1 methyl H dimethylamino(Z)-3-{1-[4-dimethylaminomethyl-phenylamino]-1-phenyl- 240-242 methylmethylidene}-5-methylsulphonylamino-2-indolinone Ex. 1 n-propyl Hdimethylamino (Z)-3-{1-[4-dimethylaminomethyl-phenylamino]-1-phenyl-221-223 methyl methylidene}-5-n-propylsulphonylamino-2-indolinone Ex. 1n-butyl H dimethylamino-(Z)-3-{1-[4-dimethylaminomethyl-phenylamino]-1-phenyl- 210-213 methylmethylidene}-5-n-butylsulphonylamino-2-indolinone Ex. 1 ethyl Hdiethylamino- (Z)-3-{1-[4-diethylaminomethyl-phenylamino]-1-phenyl-182-185 methyl methylidene}-5-ethylsulphonylamino-2-indolinone Ex. 1ethyl H N-(2-dimethyl- (Z)-3-{1-[4-(N-(2-dimethylaminoethyl)-N- 201-203aminoethyl)-N- methylaminocarbonyl)-phenylamino]-1-phenyl- methylamino-methylidene}-5-ethylsulphonylamino-2-indolinone carbonyl Ex. 210 ethylCH₃ dimethylamino- (Z)-3-[1-(4-dimethylaminomethyl-phenylamino)-1-phenylmethyl methylidene]-5-(N-ethyl-N-phenylsulphonyl-amino)-2- indolinoneEx. 1 pyrid-2-yl H (S)-2-hydroxy-(Z)-3-{1-[4-((S)-2-hydroxymethylpyrrolid-1-ylmethyl)- sintering methyl-phenylamino]-1-phenyl-methylidene}-5-pyrid-2- from 100 pyrrolidin-1-ylsulphonylamino-2-indolinone ylmethyl Ex. 1 pyrid-2-yl H (S)-3-hydroxy-(Z)-3-{1-[4-((S)-3-hydroxypyrrolid-1-ylmethyl)- sintering pyrrolidin-1-phenylamino]-1-phenyl-methylidene}-5-pyrid-2- from 130 ylmethylylsulphonylamino-2-indolinone

EXAMPLE 207

[0568](Z)-3-{1-[4-(N-(2-dimethylamino-ethyl)-N-methylsulphonyl-amino)-phenylamino)-1-phenyl-methylidene}-5-(N-methyl-N-phenylsulphonyl-amino)-2-indolinone

[0569] a.(Z)-1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5-(N-methyl-N-phenylsulphonyl-amino)-2-indolinone

[0570] 10 g (20 mmol) of1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5-(N-acetyl-N-phenylsulphonyl-amino)-2-indolinone(Example Ie) are dissolved in 150 ml of DMSO and combined with 2.2 g (20mmol) of potassium tert. butoxide with stirring. After 15 minutes'stirring 1.9 ml (31 mmol) of iodomethane are added. The mixture isstirred for 3 hours at ambient temperature. Then another 2.2 g (20 mmol)of potassium tert. butoxide and 1 ml (16 mmol) of iodomethane are added.The mixture is stirred for 18 hours at ambient temperature. Then wateris added. The reaction mixture is extracted with ethyl acetate. Theorganic phase is washed with water, dried over magnesium sulphate andevaporated to dryness. The residue is chromatographed on silica gel(petroleum ether/dichloromethane, 7:3).

[0571] Yield: 2.7 g (28% of theory)

[0572] R_(f) value: 0.65 (silica gel; dichloromethane/petroleumether=8:2)

[0573] C₂₆H₂₄N₂O₅S (476.56)

[0574] Mass spectrum: (M+Na)⁺=499

[0575] b.(Z)-3-{1-[4-(N-(2-dimethylamino-ethyl)-N-methylsulphonyl-amino)-phenylamino)-1-phenyl-methylidene}-5-(N-methyl-N-phenylsulphonyl-amino)-2-indolinone

[0576] Prepared analogously to Example If from 350 mg (0.73 mmol) of(Z)-1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5-(N-methyl-N-phenylsulphonyl-amino)-2-indolinoneand 257 mg (1 mmol) of4-[N-(2-dimethylamino-ethyl)-N-methylsulphonyl-amino]-aniline in DMF andsubsequent treatment with sodium hydroxide solution.

[0577] Yield: 380 mg (80% of theory)

[0578] R_(f) value: 0.5 (silica gel;dichloromethane/methanol/NH₄OH=9:1:0.1)

[0579] C₃₃H₃₅N₅O₅S₂ (645.80)

[0580] Mass spectrum: M⁺=645 Calc.: C 61.38 H 5.46 N 10.84 Found: C61.09 H 5.45 N 10.82

[0581] The following compounds of Examples 208 to 210 are preparedanalogously to Example 207 using the intermediate products prepared inExamples I to XIII:

EXAMPLE 208

[0582](Z)-3-{1-[4-(N-(2-dimethylamino-ethyl)-N-acetyl-amino)-phenylamino)-1-phenyl-methylidene}-5-(N-methyl-N-phenylsulphonyl-amino)-2-indolinone

[0583] Melting point: 217° C.

[0584] R_(f) value: 0.5 (silica gel;dichloromethane/methanol/NH₄OH=9:1:0.1)

[0585] C₃₄H₃₅N₅O₄S (609.75)

[0586] Mass spectrum: (M+H)⁺=610 Calc.: C 66.97 H 5.79 N 11.49 Found: C66.92 H 5.78 N 11.39

EXAMPLE 209

[0587](Z)-3-{1-[4-(N-methyl-N-piperidinomethylcarbonyl-amino)-phenylamino)-1-phenyl-methylidene}-5-(N-methyl-N-phenylsulphonyl-amino)-2-indolinone

[0588] Melting point: 160° C.

[0589] R_(f) value: 0.65 (silica gel;dichloromethane/methanol/NH₄OH=9:1:0.1)

[0590] C₃₆H₃₇N₅O₄S (635.79)

[0591] Mass spectrum: (M+H)⁺=636

EXAMPLE 210

[0592](Z)-3-[1-(3-dimethylaminomethyl-phenylamino)-1-phenyl-methylidene]-5-(N-methyl-N-phenylsulphonyl-amino)-2-indolinone

[0593] Melting point: 226° C.

[0594] R_(f) value: 0.75 (silica gel;dichloromethane/methanol/NH₄OH=9:1:0.1)

[0595] C₃₁H₃₀N₄O₃S (538.67)

[0596] Mass spectrum: (M+H)⁺=539

[0597] The following compounds may be obtained analogously to theforegoing Examples:

[0598] (1)(Z)-3-[1-(3-dimethylaminomethyl-phenylamino)-1-phenyl-methylidene]-5-ethylsulphonylamino-2-indolinone,melting point 222-224° C.

[0599] (2)(Z)-3-{1-[4-(2-dimethylaminoethyl)-phenylamino]-1-phenyl-methylidene}-5-methylsulphonylamino-2-indolinone

[0600] (3)(Z)-3-[1-(4-diethylaminomethyl-phenylamino)-1-phenyl-methylidene]-5-methylsulphonylamino-2-indolinone

[0601] (4)(Z)-3-[1-(4-dipropylaminomethyl-phenylamino)-1-phenyl-methylidene]-5-methylsulphonylamino-2-indolinone

[0602] (5)(Z)-3-[1-(4-hexamethyleneiminomethyl-phenylamino)-1-phenyl-methylidene]-5-methylsulphonylamino-2-indolinone

[0603] (6)(Z)-3-{1-[4-(4-methylpiperidinomethyl)-phenylamino]-1-phenyl-methylidene}-5-methylsulphonylamino-2-indolinone

[0604] (7)(Z)-3-[1-(4-morpholinomethyl-phenylamino)-1-phenyl-methylidene]-5-methylsulphonylamino-2-indolinone

[0605] (8)(Z)-3-{1-[4-(4-methylpiperazinomethyl)-phenylamino]-1-phenyl-methylidene}-5-methylsulphonylamino-2-indolinone

[0606] (9)(Z)-3-[1-(4-piperazinomethyl-phenylamino)-1-phenyl-methylidene]-5-methylsulphonylamino-2-indolinone

[0607] (10)(Z)-3-{1-[4-(2,6-dimethylpiperidinomethyl)-phenylamino]-1-phenyl-methylidene}-5-methylsulphonylamino-2-indolinone

[0608] (11)(Z)-3-[1-(4-dipropylaminomethyl-phenylamino)-1-phenyl-methylidene]-5-ethylsulphonylamino-2-indolinone

[0609] (12)(Z)-3-[1-(4-hexamethyleneiminomethyl-phenylamino)-1-phenyl-methylidene]-5-ethylsulphonylamino-2-indolinone

[0610] (13)(Z)-3-{1-[4-(4-methylpiperidinomethyl)-phenylamino]-1-phenyl-methylidene}-5-ethylsulphonylamino-2-indolinone

[0611] (14)(Z)-3-[1-(4-morpholinomethyl-phenylamino)-1-phenyl-methylidene]-5-ethylsulphonylamino-2-indolinone

[0612] (15)(Z)-3-{1-[4-(4-methylpiperazinomethyl)-phenylamino]-1-phenyl-methylidene}-5-ethylsulphonylamino-2-indolinone

[0613] (16)(Z)-3-[1-(4-piperazinomethyl-phenylamino)-1-phenyl-methylidene]-5-ethylsulphonylamino-2-indolinone

[0614] (17)(Z)-3-{1-[4-(2,6-dimethylpiperidinomethyl)-phenylamino]-1-phenyl-methylidene}-5-ethylsulphonylamino-2-indolinone

[0615] (18)(Z)-3-[1-(4-piperazinomethyl-phenylamino)-1-phenyl-methylidene]-5-propylsulphonylamino-2-indolinone

[0616] (19)(Z)-3-{1-[4-(2,6-dimethylpiperidinomethyl)-phenylamino]-1-phenyl-methylidene}-5-propylsulphonylamino-2-indolinone

[0617] (20)(Z)-3-[1-(4-diethylaminomethyl-phenylamino)-1-phenyl-methylidene]-5-propylsulphonylamino-2-indolinone

[0618] (21)(Z)-3-[1-(4-dipropylaminomethyl-phenylamino)-1-phenyl-methylidene]-5-propylsulphonylamino-2-indolinone

[0619] (22)(Z)-3-[1-(4-hexamethyleneiminomethyl-phenylamino)-1-phenyl-methylidene]-5-propylsulphonylamino-2-indolinone

[0620] (23)(Z)-3-{1-[4-(4-methylpiperidinomethyl)-phenylamino]-1-phenyl-methylidene}-5-propylsulphonylamino-2-indolinone

[0621] (24)(Z)-3-[1-(4-morpholinomethyl-phenylamino)-1-phenyl-methylidene]-5-propylsulphonylamino-2-indolinone

[0622] (25)(Z)-3-{1-[4-(4-methylpiperazinomethyl)-phenylamino]-1-phenyl-methylidene}-5-propylsulphonylamino-2-indolinone

[0623] (26)(Z)-3-[1-(4-piperazinomethyl-phenylamino)-1-phenyl-methylidene]-5-cyclopropylsulphonylamino-2-indolinone

[0624] (27)(Z)-3-{1-[4-(2,6-dimethylpiperidinomethyl)-phenylamino]-1-phenyl-methylidene}-5-cyclopropylsulphonylamino-2-indolinone

[0625] (28)(Z)-3-[1-(4-dimethylaminomethyl-phenylamino)-1-phenyl-methylidene]-5-cyclopropylsulphonylamino-2-indolinone

[0626] (29)(Z)-3-{1-[4-(2-dimethylaminoethyl)-phenylamino]-1-phenyl-methylidene}-5-cyclopropylsulphonylamino-2-indolinone

[0627] (30)(Z)-3-[1-(4-diethylaminomethyl-phenylamino)-1-phenyl-methylidene]-5-cyclopropylsulphonylamino-2-indolinone

[0628] (31)(Z)-3-[1-(4-dipropylaminomethyl-phenylamino)-1-phenyl-methylidene]-5-cyclopropylsulphonylamino-2-indolinone

[0629] (32)(Z)-3-[1-(4-hexamethyleneiminomethyl-phenylamino)-1-phenyl-methylidene]-5-cyclopropylsulphonylamino-2-indolinone

[0630] (33)(Z)-3-{1-[4-(4-methylpiperidinomethyl)-phenylamino]-1-phenyl-methylidene}-5-cyclopropylsulphonylamino-2-indolinone

[0631] (34)(Z)-3-[1-(4-morpholinomethyl-phenylamino]-1-phenyl-methylidene)-5-cyclopropylsulphonylamino-2-indolinone

[0632] (35)(Z)-3-{1-[4-(4-methylpiperazinomethyl)-phenylamino]-1-phenyl-methylidene}-5-cyclopropylsulphonylamino-2-indolinone

[0633] (36)(Z)-3-[1-(4-piperazinomethyl-phenylamino)-1-phenyl-methylidene]-5-trifluoromethylsulphonylamino-2-indolinone

[0634] (37)(Z)-3-{1-[4-(2,6-dimethylpiperidinomethyl)-phenylamino]-1-phenyl-methylidene}-5-trifluoromethylsulphonylamino-2-indolinone

[0635] (38)(Z)-3-[1-(4-dimethylaminomethyl-phenylamino)-1-phenyl-methylidene]-5-trifluoromethylsulphonylamino-2-indolinone

[0636] (39)(Z)-3-{1-[4-(2-dimethylaminoethyl)-phenylamino]-1-phenyl-methylidene}-5-trifluoromethylsulphonylamino-2-indolinone

[0637] (40)(Z)-3-[1-(4-diethylaminomethyl-phenylamino)-1-phenyl-methylidene]-5-trifluoromethylsulphonylamino-2-indolinone

[0638] (41)(Z)-3-[1-(4-dipropylaminomethyl-phenylamino)-1-phenyl-methylidene]-5-trifluoromethylsulphonylamino-2-indolinone

[0639] (42)(Z)-3-{1-[4-(pyrrolidin-1-yl)-methyl-phenylamino]-1-phenyl-methylidene}-5-trifluoromethylsulphonylamino-2-indolinone

[0640] (43)(Z)-3-[1-(4-piperidinomethyl-phenylamino)-1-phenyl-methylidene]-5-trifluoromethylsulphonylamino-2-indolinone

[0641] (44)(Z)-3-[1-(4-hexamethyleneiminomethyl-phenylamino)-1-phenyl-methylidene]-5-trifluoromethylsulphonylamino-2-indolinone

[0642] (45)(Z)-3-{1-[4-(4-methylpiperidinomethyl)-phenylamino]-1-phenyl-methylidene}-5-trifluoromethylsulphonylamino-2-indolinone

[0643] (46)(Z)-3-[1-(4-morpholinomethyl-phenylamino)-1-phenyl-methylidene]-5-trifluoromethylsulphonylamino-2-indolinone

[0644] (47)(Z)-3-{1-[4-(4-methylpiperazinomethyl)-phenylamino]-1-phenyl-methylidene}-5-trifluoromethylsulphonylamino-2-indolinone

[0645] (48)(Z)-3-[1-(4-piperazinomethyl-phenylamino)-1-phenyl-methylidene]-5-isopropylsulphonylamino-2-indolinone

[0646] (49)(Z)-3-{1-[4-(2,6-dimethylpiperidinomethyl)-phenylamino]-1-phenyl-methylidene}-5-isopropylsulphonylamino-2-indolinone

[0647] (50)(Z)-3-[1-(4-dimethylaminomethyl-phenylamino)-1-phenyl-methylidene]-5-isopropylsulphonylamino-2-indolinone

[0648] (51)(Z)-3-[1-(4-diethylaminomethyl-phenylamino)-1-phenyl-methylidene]-5-isopropylsulphonylamino-2-indolinone

[0649] (52)(Z)-3-[1-(4-dipropylaminomethyl-phenylamino)-1-phenyl-methylidene]-5-isopropylsulphonylamino-2-indolinone

[0650] (53)(Z)-3-{1-[4-(pyrrolidin-1-yl)-methyl-phenylamino]-1-phenyl-methylidene}-5-isopropylsulphonylamino-2-indolinone

[0651] (54)(Z)-3-[1-(4-hexamethyleneiminomethyl-phenylamino)-1-phenyl-methylidene]-5-isopropylsulphonylamino-2-indolinone

[0652] (55)(Z)-3-{1-[4-(4-methylpiperidinomethyl)-phenylamino]-1-phenyl-methylidene}-5-isopropylsulphonylamino-2-indolinone

[0653] (56)(Z)-3-[1-(4-morpholinomethyl-phenylamino)-1-phenyl-methylidene]-5-isopropylsulphonylamino-2-indolinone

[0654] (57)(Z)-3-{1-[4-(4-methylpiperazinomethyl)-phenylamino]-1-phenyl-methylidene}-5-isopropylsulphonylamino-2-indolinone

EXAMPLE 211

[0655] Dry ampoule containing 75 mg of active substance per 10 ml

[0656] Composition: Active substance 75.0 mg Mannitol 50.0 mg water forinjections ad 10.0 ml

[0657] Preparation:

[0658] Active substance and mannitol are dissolved in water. Afterpackaging the solution is freeze-dried. To produce the solution readyfor use, the product is dissolved in water for injections.

EXAMPLE 212

[0659] Dry ampoule containing 35 mg of active substance per 2 ml

[0660] Composition: Active substance  35.0 mg Mannitol 100.0 mg waterfor injections ad  2.0 ml

[0661] Preparation:

[0662] Active substance and mannitol are dissolved in water. Afterpackaging, the solution is freeze-dried.

[0663] To produce the solution ready for use, the product is dissolvedin water for injections.

EXAMPLE 213

[0664] Tablet containing 50 mg of active substance

[0665] Composition: (1) Active substance  50.0 mg (2) Lactose  98.0 mg(3) Maize starch  50.0 mg (4) Polyvinylpyrrolidone  15.0 mg (5)Magnesium stearate  2.0 mg 215.0 mg

[0666] Preparation:

[0667] (1), (2) and (3) are mixed together and granulated with anaqueous solution of (4). (5) is added to the dried granulated material.From this mixture tablets are pressed, biplanar, faceted on both sidesand with a dividing notch on one side.

[0668] Diameter of the tablets: 9 mm.

EXAMPLE 214

[0669] Tablet containing 350 mg of active substance

[0670] Preparation: (1) Active substance 350.0 mg (2) Lactose 136.0 mg(3) Maize starch  80.0 mg (4) Polyvinylpyrrolidone  30.0 mg (5)Magnesium stearate  4.0 mg 600.0 mg

[0671] (1), (2) and (3) are mixed together and granulated with anaqueous solution of (4). (5) is added to the dried granulated material.From this mixture tablets are pressed, biplanar, faceted on both sidesand with a dividing notch on one side.

[0672] Diameter of the tablets: 12 mm.

EXAMPLE 215

[0673] Capsules containing 50 mg of active substance

[0674] Composition: (1) Active substance  50.0 mg (2) Dried maize starch 58.0 mg (3) Powdered lactose  50.0 mg (4) Magnesium stearate  2.0 mg160.0 mg

[0675] Preparation:

[0676] (1) is triturated with (3). This trituration is added to themixture of (2) and (4) with vigorous mixing.

[0677] This powder mixture is packed into size 3 hard gelatine capsulesin a capsule filling machine.

EXAMPLE 216

[0678] Capsules containing 350 mg of active substance

[0679] Composition: (1) Active substance 350.0 mg (2) Dried maize starch 46.0 mg (3) Powdered lactose  30.0 mg (4) Magnesium stearate  4.0 mg430.0 mg

[0680] Preparation:

[0681] (1) is triturated with (3). This trituration is added to themixture of (2) and (4) with vigorous mixing.

[0682] This powder mixture is packed into size 0 hard gelatine capsulesin a capsule filling machine.

EXAMPLE 217

[0683] Suppositories containing 100 mg of active substance 1 suppositorycontains: active substance   100.0 mg polyethyleneglycol (M.W. 1500)  600.0 mg polyethyleneglycol (M.W. 6000)   460.0 mgpolyethylenesorbitan monostearate   840.0 mg 2,000.0 mg

[0684] Preparation:

[0685] The polyethyleneglycol is melted together with polyethylenesorbitan monostearate. At 40° C. the ground active substance ishomogeneously dispersed in the melt. It is cooled to 38° C. and pouredinto slightly chilled suppository moulds.

What is claimed is:
 1. A compound of the formula I

or a pharmaceutically acceptable salt thereof, wherein: X is an oxygenor sulphur atom, R₁ is a hydrogen atom, a C₁₋₄-alkoxycarbonyl orC₂₋₄-alkanoyl group, R₂ is a C₁₋₆-alkyl group optionally substituted byone or more halogen atoms or a phenyl group or a C₂₋₆-alkenyl groupoptionally substituted by a phenyl group, wherein the phenyl moiety maybe substituted in each case by a fluorine, chlorine, bromine or iodineatom, by a C₁₋₃-alkyl or C₁₋₃-alkoxy group, a phenyl group which may bemono- or disubstituted by fluorine, chlorine, bromine or iodine atoms,by C₁₋₃-alkyl or C₁₋₃-alkoxy groups, wherein the substituents may beidentical or different, a phenyl group substituted by a trifluoromethyl,carboxy, C₁₋₃-alkoxycarbonyl, aminocarbonyl, cyano, aminomethyl, nitroor amino group, a C₄₋₆-alkyl, C₃₋₇-cycloalkyl, trimethylphenyl ornaphthyl group, a 5-membered heteroaromatic group optionally substitutedby a C₁₋₃-alkyl group, which contains, in the heteroaromatic moiety, animino group optionally substituted by a C₁₋₃-alkyl group, an oxygen orsulphur atom, an imino group optionally substituted by a C₁₋₃-alkylgroup and an oxygen, sulphur or nitrogen atom, an imino group optionallysubstituted by a C₁₋₃-alkyl group and two nitrogen atoms, or an oxygenor sulphur atom and two nitrogen atoms, and to which a phenyl ring maybe fused via two adjacent carbon atoms, or is a 6-memberedheteroaromatic group optionally substituted by a C₁₋₃-alkyl group, whichcontains one or two heteroatoms in the heteroaromatic moiety and towhich a phenyl ring may be fused via two adjacent carbon atoms, R₃ is ahydrogen atom or a C₁₋₆alkyl group, a phenyl group optionallysubstituted by a fluorine, chlorine or bromine atom, by a C₁₋₃-alkyl,hydroxy, C₁₋₃-alkoxy, C₁₋₃-alkylsulphenyl, C₁₋₃-alkylsulphinyl,C₁₋₃-alkylsulphonyl, phenylsulphenyl, phenylsulphinyl, phenylsulphonyl,nitro, amino, C₁₋₃-alkylamino, di-(C₁₋₃-alkyl)-amino, C₂₋₅-alkanoylaminoor N—(C₁₋₃-alkylamino)-C₂₋₅-alkanoylamino group, R₄ is a phenyl ornaphthyl group optionally substituted by R₇, which may additionally besubstituted by a chlorine or bromine atom or a nitro group, a 5-memberedheteroaromatic group which contains an imino group, an oxygen or sulphuratom or an imino group, an oxygen or sulphur atom and one or twonitrogen atoms, or a 6-membered heteroaromatic group which contains one,two or three nitrogen atoms, while the abovementioned 5- and 6-memberedheteroaromatic groups may additionally be substituted by a chlorine orbromine atom or by a methyl group or wherein a phenyl ring may be fusedto the abovementioned 5- and 6-membered heteroaromatic groups via 2adjacent carbon atoms, or R₅ and R₆ in each case independently of oneanother are hydrogen atoms or C₁₋₃-alkyl groups, and R₇ is a fluorine,chlorine, bromine or iodine atom or a cyano group, a methoxy group or aC₂₋₃-alkoxy group, which may be substituted in the 2 or 3 position by anamino, C₁₋₃-alkylamino, di-(C₁₋₃-alkyl)-amino or 5- to 7-memberedcycloalkyleneimino group, while in each case an alkyl moiety in theabove-mentioned alkylamino and dialkylamino groups may additionally besubstituted by a phenyl group, a trifluoromethyl, nitro, amino,C₁₋₃-alkylamino, di-(C₁₋₃-alkyl)-amino, C₂₋₅-alkanoylamino,N—(C₁₋₃-alkyl)-C₂₋₅-alkanoylamino, C₁₋₅-alkylsulphonylamino,N—(C₁₋₃-alkyl)-C₁₋₅-alkylsulphonylamino, phenylsulphonylamino,N—(C₁₋₃-alkyl)-phenylsulphonylamino, aminosulphonyl,C₁₋₃-alkylaminosulphonyl or di-(C₁₋₃-alkyl)-aminosulphonyl group, whilein each case an alkyl moiety in the above-mentioned alkylamino anddialkylamino groups may additionally be substituted by a carboxy,C₁₋₃-alkoxycarbonyl, aminocarbonyl, C₁₋₃-alkylaminocarbonyl,di-(C₁₋₃-alkyl)-aminocarbonyl, 2-dimethylaminoethylaminocarbonyl orN-methyl-(2-dimethylaminoethyl)-aminocarbonyl group and in each case thealkyl moiety of the above-mentioned alkanoylamino or alkysulphonylaminogroups may additionally be substituted by a phenyl, amino,C₁₋₃-alkylamino, di-(C₁₋₃-alkyl)-amino or a 4- to 7-memberedcycloalkyleneimino group, a C₂₋₄-alkylamino group which is terminallysubstituted in the 2,3- or 4 position by an amino, C₁₋₃-alkylamino,di-(C₁₋₃-alkyl)-amino, benzylamino, N—(C₁₋₃-alkyl)-benzylamino,C₂₋₅-alkanoylamino or N—(C₁₋₃-alkyl)-C₂₋₅-alkanoylamino group andwherein additionally the amino-hydrogen atom may be replaced by aC₂₋₅-alkanoyl, benzoyl, C₁₋₅-alkylsulphonyl- or phenylsulphonyl group,while the last-mentioned C₂₋₅-alkanoyl or C₁₋₅-alkylsulphonyl groups inthe alkyl moiety may be substituted by a phenyl group, a carbonyl groupwhich is substituted by a hydroxy, C₁₋₃-alkoxy, amino, C₁₋₃-alkylamino,N—(C₁₋₅-alkyl)-C₁₋₃-alkylamino or C₅₋₇-cycloalkyleneimino group; aC₁₋₃-alkyl group which may be substituted by an amino, C₁₋₅-alkylamino,C₅₋₇-cycloalkylamino or phenyl-C₁₋₃-alkylamino group which mayadditionally be substituted at the amino nitrogen atom in each case by aC₁₋₄-alkyl, C₅₋₇-cycloalkyl or C₂₋₄-alkenyl- or C₁₋₄-alkyl group, whilethe abovementioned C₁₋₄-alkyl substituent in each case may additionallybe mono-, di- or trisubstituted by a cyano, carboxy,C₁₋₃-alkoxycarbonyl, C₂₋₄-alkanoyl, pyridyl, imidazolyl,benzo[1,3]dioxol or phenyl group, while the phenyl group may besubstituted by fluorine, chlorine or bromine atoms, by methyl, methoxy,trifluoromethyl, cyano or nitro groups and the substituents may beidentical or different, or in the 2, 3 or 4 position by a hydroxy group,a C₁₋₃-alkyl group which is substituted by a hydroxy, carboxy,morpholino, thiomorpholino, 1-oxo-thiomorpholino,1,1-dioxo-thiomorpholino, piperazino, N—(C₁₋₃-alkyl)-piperazino orN-benzyl-piperazino group, by a 5- to 7-membered cycloalkenyleneiminogroup or by a 4- to 7-membered cycloalkyleneimino group, while theabovementioned 5- to 7-membered cycloalkyleneimino groups may besubstituted by one or two C₁₋₃-alkyl groups, which may in turn beterminally substituted by a hydroxy, amino or C₂₋₄-alkanoylamino group,or by a C₅₋₇-cycloalkyl or phenyl group and by a hydroxy group and inthe abovementioned cycloalkyleneimino groups a methylene group adjacentto the nitrogen atom may be replaced by a carbonyl group, a C₁₋₃-alkylgroup which is substituted by a 5- to 7-membered cycloalkyleneiminogroup, while a phenyl group optionally mono- or disubstituted byfluorine, chlorine or bromine atoms or by methyl or methoxy groups,wherein the substituents may be identical or different, or an oxazolo,imidazolo, thiazolo, pyridino, pyrazino or pyrimidino group optionallysubstituted by a fluorine, chlorine, bromine or iodine atom, by amethyl, methoxy or amino group is fused to the abovementioned 5- to7-membered cycloalkyleneimino groups via 2 adjacent carbon atoms, whilethe above-mentioned monosubstituted phenyl groups may additionally besubstituted by a fluorine, chlorine or bromine atom, by a methyl,methoxy or nitro group, or is an imidazolyl or 1H—C₁₋₃-alkylimidazolylgroup.
 2. A compound of formula I according to claim 1 wherein thesulphonylamino group of the formula R₂—SO₂NR₆— is linked to the5-position of the indolinone group.
 3. A compound of formula I accordingto claim 1, wherein: R₃ is a phenyl group optionally substituted by afluorine, chlorine or bromine atom, by a C₁₋₃-alkyl, hydroxy,C₁₋₃-alkoxy, C₁₋₃-alkylsulphenyl, C₁₋₃-alkylsulphinyl,C₁₋₃-alkylsulphonyl, phenylsulphenyl, phenylsulphinyl, phenylsulphonyl,nitro, amino, C₁₋₃-alkylamino, di-(C₁₋₃-alkyl)-amino, C₂₋₅-alkanoylaminoor N—(C₁₋₃-alkylamino)-C₂₋₅-alkanoylamino group.
 4. A compound offormula I according to claim 1, wherein: R₂ is a C₁₋₃-alkyl groupoptionally substituted by one or more halogen atoms or a phenyl group ora C₂₋₄-alkenyl group optionally substituted by a phenyl group, whereinthe phenyl moiety in each case may be substituted by a fluorine,chlorine, bromine or iodine atom or by a C₁₋₃-alkyl or C₁₋₃-alkoxygroup.
 5. A compound of formula I according to claim 1, wherein: X is anoxygen atom, R₁ is a hydrogen atom, R₂ is a C₁₋₃-alkyl group optionallysubstituted by one or more fluorine atoms or a phenyl group or aC₂₋₄-alkenyl group optionally substituted by a phenyl group; a phenylgroup which may be mono- or disubstituted by fluorine, chlorine, bromineor iodine atoms, by C₁₋₃-alkyl or C₁₋₃-alkoxy groups, wherein thesubstituents may be identical or different, a phenyl group substitutedby a trifluoromethyl, carboxy, C₁₋₃-alkoxycarbonyl, aminocarbonyl,cyano, aminomethyl, nitro or amino group, a C₄₋₆-alkyl, C₃₋₇-cycloalkyl,trimethylphenyl or naphthyl group, or a pyridinyl, quinolyl,isoquinolyl, oxazolyl, isoxazolyl, imidazolyl or1-(C₁₋₃-alkyl)-imidazolyl group optionally substituted by a C₁₋₃-alkylgroup, R₃ is a hydrogen atom or a C₁₋₄-alkyl group, or a phenyl groupoptionally substituted by a fluorine, chlorine, bromine or iodine atom,by a C₁₋₃-alkyl, C₁₋₃-alkoxy, nitro or amino group, R₄ is a phenyl groupoptionally substituted by R₇, R₅ and R₆ in each case denote a hydrogenatom, and R₇ is a fluorine, chlorine, bromine or iodine atom, a methoxy,nitro, cyano, carboxy, C₁₋₃-alkoxycarbonyl, aminocarbonyl,C₁₋₃-alkylaminocarbonyl, di-(C₁₋₃-alkyl)-aminocarbonyl,phenyl-C₁₋₃-alkylaminocarbonyl,N-(phenyl-C₁₋₃-alkyl)-C₁₋₃-alkylaminocarbonyl or 5- to 7-memberedcycloalkyleneiminocarbonyl group, a C₁₋₃-alkyl group which issubstituted by a carboxy, C₁₋₃-alkoxycarbonyl, aminocarbonyl,C₁₋₃-alkylaminocarbonyl, di-(C₁₋₃-alkyl)-aminocarbonyl,phenyl-C₁₋₃-alkylaminocarbonyl,N-(phenyl-C₁₋₃-alkyl)-C₁₋₃-alkylaminocarbonyl, 5- to 7-memberedcycloalkyleneiminocarbonyl, amino, C₁₋₃-alkylamino,di-(C₁₋₃-alkyl)-amino, phenyl-C₁₋₃-alkylamino,N-(phenyl-C₁₋₃-alkyl)-C₁₋₃-alkylamino or 5- to 7-memberedcycloalkyleneimino group, while the abovementioned 5- to 7-memberedcycloalkyleneimino group may be substituted by one or two C₁₋₃-alkylgroups, which may in turn be terminally substituted by a hydroxy, aminoor C₂₋₄-alkanoylamino group, and at the same time in the abovementioned5- to 7-membered cycloalkyleneimino moieties a methylene group in the 2position may be replaced by a carbonyl group or in the abovementioned 6-and 7-membered cycloalkyleneimino moieties a methylene group in the 4position may be replaced by an oxygen atom, by an imino,N—(C₁₋₃-alkyl)-imino, N-(phenyl-C₁₋₃-alkyl)-imino orN—(C₁₋₅-alkoxycarbonyl)-imino group, an amino, C₁₋₃-alkylamino,phenyl-C₁₋₃-alkylamino, C₁₋₅-alkanoylamino, phenyl-C₁₋₄-alkanoylamino,C₁₋₅-alkoxycarbonylamino, phenyl-C₁₋₃-alkoxycarbonylamino,C₁₋₅-alkylsulphonylamino, phenyl-C₁₋₃-alkylsulphonylamino- orphenylsulphonylamino group, wherein the hydrogen atom of the amino groupmay be replaced by a C₁₋₃-alkyl group, while the C₁₋₃-alkyl moiety maybe substituted by a carboxy, C₁₋₃-alkoxycarbonyl, aminocarbonyl,C₁₋₃-alkylaminocarbonyl, di-(C₁₋₃-alkyl)-aminocarbonyl,phenyl-C₁₋₃-alkylaminocarbonyl,N-(phenyl-C₁₋₃-alkyl)-C₁₋₃-alkylaminocarbonyl,2-dimethylaminoethylaminocarbonyl,N-methyl-(2-dimethylaminoethyl)-aminocarbonyl- orC₄₋₆-cycoalkylenimnocarbonyl group or from position 2 by an amino,C₁₋₃-alkylamino, di-(C₁₋₃-alkyl)-amino, phenyl-C₁₋₃-alkylamino,N-(phenyl-C₁₋₃-alkyl)-C₁₋₃-alkylamino, C₂₋₅-alkanoylamino,N—(C₁₋₃-alkyl)-C₂₋₅-alkanoylamino, C₁₋₅-alkoxycarbonylamino- orN—(C₁₋₅-alkoxycarbonyl)-C₁₋₃-alkylamino group.
 6. A compound of formulaI according to claim 1, wherein: R₂ is a C₁₋₃-alkyl group optionallysubstituted by a phenyl group, a C₁₃-perfluoroalkyl group or aphenylvinyl group, a phenyl group which may be substituted by afluorine, chlorine, bromine or iodine atom, by a C₁₋₃-alkyl,C₁₋₃-alkoxy, nitro, amino, cyano, cyanomethyl or aminomethyl group, aC₄₋₆-alkyl, C₃₋₇-cycloalkyl, trimethylphenyl or naphthyl group, apyridinyl, quinolyl, isoquinolyl, oxazolyl, isoxazolyl, imidazolyl or1-(C₁₋₃-alkyl)-imidazolyl group optionally substituted by a C₁₋₃-alkylgroup, R₃ is a phenyl group optionally substituted by a fluorine,chlorine, bromine or iodine atom, by a C₁₋₃-alkyl, C₁₋₃-alkoxy, nitro oramino group, R₄ is a phenyl group which may be substituted by R₇ andadditionally by a chlorine atom or a nitro group, while R₇ is afluorine, chlorine, bromine or iodine atom, a methoxy, nitro, cyano,carboxy, methoxycarbonyl, aminocarbonyl, methylaminocarbonyl,dimethylaminocarbonyl, benzylaminocarbonyl,N-benzyl-methylaminocarbonyl, pyrrolidinocarbonyl or piperidinocarbonylgroup, a methyl or ethyl group which may be substituted by a carboxy,methoxycarbonyl, aminocarbonyl, methylaminocarbonyl,dimethylaminocarbonyl, benzylaminocarbonyl,N-benzyl-methylaminocarbonyl, pyrrolidinocarbonyl, piperidinocarbonyl,amino, methylamino, dimethylamino, benzylamino, N-benzylmethylamino,C₂₋₄-alkanoylamino, N-methyl-C₂₋₄-alkanoylamino,tert.butyloxycarbonylamino, N-methyl-tert.butyloxycarbonylamino,pyrrolidino, pyrrolidinomethyl, hydroxypyrrolidinomethyl,hydroxymethylpyrrolidinomethyl, piperidino, dimethylpiperidino,2-oxo-piperidino, piperazino, 4-methyl-piperazino, 4-benzyl-piperazino,4-tert.butoxycarbonyl-piperazino or morpholino group, or an amino,methylamino, ethylamino, C₁₋₃-alkanoylamino, phenylacetylamino,tert.butoxycarbonylamino, C₁₋₄-alkylsulphonylamino,phenyl-methylsulphonylamino or phenylsulphonylamino group, wherein thehydrogen atom of the amino group may be replaced by a methyl or ethylgroup, while the methyl or ethyl moiety in each case may be substitutedby a carboxy, methoxycarbonyl, aminocarbonyl, methylaminocarbonyl ordimethylaminocarbonyl group or the ethyl moiety may also be substitutedfrom position 2 by an amino, methylamino, dimethylamino,benzylalkylamino, N-benzyl-methylamino, C₂₋₃-alkanoylamino,N-methyl-C₂₋₃-alkanoylamino, tert.butyloxycarbonylamino orN-methyl-tert.butyloxycarbonylamino group.
 7. A compound of formula Iaccording to claim 1, wherein R₄ is a phenyl group substituted in the 4position by R₇.
 8. A compound of the formula IA

wherein R₇ is defined as in claim 1, 5 or
 6. 9. A compound of formula IAaccording to claim 8 wherein R₇ is selected from the group consistingof: hydrogen, (2,6-dimethylpiperidino)-methyl,(N-ethylsulphonyl)-N-(2-dimethylaminoethyl)-aminocarbonylmethyl)-amino,N-ethylsulphonyl-N-(N-(2-dimethylaminoethyl)-N-methyl-amino-carbonylmethyl)-amino,2-oxopiperidinomethyl, 4-benzyl-piperazino-methyl,4-methylpiperazino-methyl, 4-tert.butoxycarbonyl-piperazinomethyl,acetylamino, acetylaminomethyl, amino, aminomethyl, benzylaminocarbonyl,benzylaminocarbonyl-methyl, carboxy, carboxymethyl, chlorine, cyano,dimethylaminocarbonyl-methylamino, dimethylaminoethyl,dimethylaminomethyl, ethoxycarbonylmethyl, ethylsulphonylamino,formylamino, methoxycarbonyl, methylsulphonylamino, morpholinomethyl,N-(2-(N-acetyl-N-methyl-amino)-ethyl)-ethylsulphonylamino,N-(2-(N-acetyl-N-methyl-amino)-ethyl)-methylsulphonylamino,N-(2-(N-acetyl-N-methyl-amino)-ethyl)-propionylamino,N-(2-(N-acetyl-N-methyl-amino)-ethylamino,N-(2-(N-benzyl-N-methyl-amino)-ethyl)-propionylamino,N-(2-acetylamino-ethyl)-N-acetyl-amino,N-(2-acetylamino-ethyl)-N-ethylsulphonyl-amino,N-(2-acetylamino-ethyl)-N-methylsulphonyl-amino,N-(2-acetylamino-ethyl)-N-propionyl-amino,N-(2-aminoethyl)-N-methylsulphonyl-amino,N-(2-dimethylamino-ethyl)-N-acetyl-amino,N-(2-dimethylamino-ethyl)-N-butylsulphonyl-amino,N-(2-dimethylamino-ethyl)-N-methylsulphonyl-amino,N-(2-dimethylamino-ethyl)-N-phenylsulphonyl-amino,N-(2-dimethylaminoethyl)-N-propylsulphonyl-amino,N-(2-methylamino-ethyl)-acetylamino,N-(2-methylamino-ethyl)-N-methylsulphonyl-amino,N-(2-methylamino-ethyl)-propionylamino,N-(2-propionylamino-ethyl)-N-propionyl-amino,N-(aminocarbonyl-methyl)-N-methylsulphonyl-amino,N-(dimethylamino-carbonylmethyl)-N-(methylsulphonyl-amino,N-(dimethylaminoethyl)-N-methylsulphonyl-amino,N-(methylaminocarbonyl-methyl)-N-methylsulphonyl-amino,N-(piperidinomethyl-carbonyl)-N-methyl-amino,N-acetyl-N-(2-(N-benzyl-N-methyl-amino)-ethylamino,N-acetyl-N-(2-benzyl-oxycarbonylamino-ethyl)-amino,N-carboxylmethyl-N-methylsulphonyl-amino,N-ethylsulphonyl-N-hydroxycarbonylmethyl-amino, N-methyl-N-acetyl-amino,N-methyl-N-ethylsulphonyl-amino, N-methyl-N-formyl-amino,N-methyl-N-methylsulphonyl-amino, N-methyl-N-propionyl-amino,piperazinomethyl, propionylamino, pyrrolidin-1-yl-methyl,2-hydroxymethylpyrrolidin-1-yl-methyl, 3-hydroxypyrrolidin-1-yl-methyland tert.butoxycarbonylamino.
 10. A compound of formula IB

wherein R₂ and R₇ are defined as in claim 1, 4, 5 or
 6. 11. A compoundof formula IB according to claim 10 wherein: R₇ is selected from thegroup consisting of: hydrogen, (2,6-dimethylpiperidino)-methyl,(N-ethylsulphonyl)-N-(2-dimethylaminoethyl)-aminocarbonylmethyl)-amino,N-ethylsulphonyl-N-(N-(2-dimethylaminoethyl)-N-methyl-amino-carbonylmethyl)-amino,2-oxopiperidinomethyl, 4-benzyl-piperazino-methyl,4-methylpiperazino-methyl, 4-tert.butoxycarbonyl-piperazinomethyl,acetylamino, acetylaminomethyl, amino, aminomethyl, benzylaminocarbonyl,benzylaminocarbonyl-methyl, carboxy, carboxymethyl, chlorine, cyano,dimethylaminocarbonyl-methylamino, dimethylaminoethyl,dimethylaminomethyl, ethoxycarbonylmethyl, ethylsulphonylamino,formylamino, methoxycarbonyl, methylsulphonylamino, morpholinomethyl,N-(2-(N-acetyl-N-methyl-amino)-ethyl)-ethylsulphonylamino,N-(2-(N-acetyl-N-methyl-amino)-ethyl)-methylsulphonylamino,N-(2-(N-acetyl-N-methyl-amino)-ethyl)-propionylamino,N-(2-(N-acetyl-N-methyl-amino)-ethylamino,N-(2-(N-benzyl-N-methyl-amino)-ethyl)-propionylamino,N-(2-acetylamino-ethyl)-N-acetyl-amino,N-(2-acetylamino-ethyl)-N-ethylsulphonyl-amino,N-(2-acetylamino-ethyl)-N-methylsulphonyl-amino,N-(2-acetylamino-ethyl)-N-propionyl-amino,N-(2-aminoethyl)-N-methylsulphonyl-amino,N-(2-dimethylamino-ethyl)-N-acetyl-amino,N-(2-dimethylamino-ethyl)-N-butylsulphonyl-amino,N-(2-dimethylamino-ethyl)-N-methylsulphonyl-amino,N-(2-dimethylamino-ethyl)-N-phenylsulphonyl-amino,N-(2-dimethylaminoethyl)-N-propylsulphonyl-amino,N-(2-methylamino-ethyl)-acetylamino,N-(2-methylamino-ethyl)-N-methylsulphonyl-amino,N-(2-methylamino-ethyl)-propionylamino,N-(2-propionylamino-ethyl)-N-propionyl-amino,N-(aminocarbonyl-methyl)-N-methylsulphonyl-amino,N-(dimethylamino-carbonylmethyl)-N-(methylsulphonyl-amino,N-(dimethylaminoethyl)-N-methylsulphonyl-amino,N-(methylaminocarbonyl-methyl)-N-methylsulphonyl-amino,N-(piperidinomethyl-carbonyl)-N-methyl-amino,N-acetyl-N-(2-(N-benzyl-N-methyl-amino)-ethylamino,N-acetyl-N-(2-benzyl-oxycarbonylamino-ethyl)-amino,N-carboxylmethyl-N-methylsulphonyl-amino,N-ethylsulphonyl-N-hydroxycarbonylmethyl-amino, N-methyl-N-acetyl-amino,N-methyl-N-ethylsulphonyl-amino, N-methyl-N-formyl-amino,N-methyl-N-methylsulphonyl-amino, N-methyl-N-propionyl-amino,piperazinomethyl, propionylamino, pyrrolidin-1-yl-methyl,2-hydroxymethylpyrrolidin-1-yl-methyl, 3-hydroxypyrrolidin-1-yl-methyland tert.butoxycarbonylamino; and R₂ is selected from the groupconsisting of: 1-methyl-1H-imidazol-4-yl, 2-aminophenyl, 2-chlorophenyl,2-cyanophenyl, 2-nitrophenyl, 2-phenylethene, 3-aminomethylphenyl,3-aminophenyl, 3-chlorophenyl, 3-cyanophenyl, 3-methoxyphenyl,3-methylphenyl, 3-nitrophenyl, 4-aminophenyl, 4-chlorophenyl,4-methoxyphenyl, 4-methylphenyl, 4-nitrophenyl, benzyl, quinolin-8-yl,cyclopropyl, ethyl, isopropyl, methyl, naphthalin-1-yl, naphthalin-2-yl,propyl, pyrid-2-yl, pyrid-3-yl, 3,5-dimethyl-isoxazol-4-yl and2,4,6-trimethylphenyl.
 12. A compound selected from the group consistingof:(Z)-3-{1-[4-(N-(2-aminoethyl)-N-methylsulphonyl-amino)-phenylamino]-1-phenyl-methylidene}-5-phenylsulphonylamino-2-indolinone,(Z)-3-{1-[4-(N-(2-dimethylaminoethyl)-N-phenylsulphonyl-amino)-phenylamino)-1-phenyl-methylidene}-5-phenylsulphonylamino-2-indolinone,(Z)-3-{1-[4-(4-methylpiperazinomethyl)-phenylamino]-1-phenyl-methylidene}-5-phenylsulphonylamino-2-indolinone,(Z)-3-{1-[4-(pyrrolidin-1-ylmethyl)-phenylamino]-1-phenyl-methylidene}-5-phenylsulphonylamino-2-indolinone,(Z)-3-{1-[4-(N-methyl-N-acetyl-amino)-phenylamino]-1-phenyl-methylidene}-5-phenylsulphonylamino-2-indolinone,(Z)-3-(1-phenylamino-1-phenyl-methylidene)-5-phenylsulphonylamino-2-indolinone,(Z)-3-[1-(4-chlorophenylamino)-1-phenyl-methylidene]-5-phenylsulphonylamino-2-indolinone,(Z)-3-{1-[4-(N-(2-propionylamino-ethyl)-N-propionyl-amino)-phenylamino]-1-phenyl-methylidene}-5-phenylsulphonylamino-2-indolinone,(Z)-3-[1-(4-dimethylaminomethyl-phenylamino)-1-phenyl-methylidene]-5-phenylsulphonylamino-2-indole,(Z)-3-[1-(4-(N-methyl-N-methylsulphonyl-amino)-phenylamino)-1-phenyl-methylidene]-5-phenylsulphonylamino-2-indolinone,(Z)-3-[1-(4-(N-methyl-N-piperidinomethylcarbonyl-amino)-phenylamino)-1-phenyl-methylidene]-5-phenylsulphonylamino-2-indolinone,(Z)-3-{1-[4-(pyrrolidin-1-ylmethyl)-phenylamino]-1-phenyl-methylidene}-5-benzylsulphonylamino-2-indolinone,(Z)-3-{1-[4-((2,6-dimethylpiperidino)-methyl)-phenylamino]-1-phenyl-methylidene}-5-(3-nitrophenylsulphonylamino)-2-indolinone,(Z)-3-{1-[4-dimethylaminomethyl-phenylamino]-1-phenyl-methylidene}-5-ethylsulphonylamino-2-indolinone,(Z)-3-{1-[4-(N-benzyl-N-methyl-aminomethyl)-phenylamino]-1-phenyl-methylidene}-5-ethylsulphonylamino-2-indolinone,(Z)-3-{1-[4-(2-dimethylamino-ethyl)-phenylamino]-1-phenyl-methylidene}-5-ethylsulphonylamino-2-indolinone,(Z)-3-{1-[4-(pyrrolidin-1-ylmethyl)-phenylamino]-1-phenyl-methylidene}-5-(pyridin-3-ylsulphonylamino)-2-indolinone,(Z)-3-{1-[4-(pyrrolidin-1-ylcarbonyl)-phenylamino]-1-phenyl-methylidene}-5-(pyridin-3-ylsulphonylamino)-2-indolinone,(Z)-3-[1-(4-piperidinomethyl-phenylamino)-1-phenyl-methylidene]-5-methylsulphonylamino-2-indolinone(Z)-3-{1-[4-(piperidinomethyl)-phenylamino]-1-phenyl-methylidene}-5-ethylsulphonylamino-2-indolinone,(Z)-3-{1-[4-(piperidinomethyl)-phenylamino]-1-phenyl-methylidene}-5-isopropylsulphonylamino-2-indolinone,(Z)-3-{1-[4-(piperidinomethyl)-phenylamino]-1-phenyl-methylidene}-5-(naphthalin-1-ylsulphonylamino)-2-indolinone,(Z)-3-{1-[4-(piperidinomethyl)-phenylamino]-1-phenyl-methylidene}-5-(3-nitrophenylsulphonylamino)-2-indolinone,(Z)-3-{1-[4-(piperidinomethyl)-phenylamino]-1-phenyl-methylidene}-5-(3,5-dimethylisoxazol-4-ylsulphonylamino)-2-indolinone,(Z)-3-{1-[4-(piperidinomethyl)-phenylamino]-1-phenyl-methylidene}-5-cyclopropylsulphonylamino-2-indolinone,(Z)-3-{1-[4-(piperidinomethyl)-phenylamino]-1-phenyl-methylidene}-5-(pyridin-3-ylphenylsulphonylamino)-2-indolinone,(Z)-3-{1-[4-(pyrrolidin-1-ylmethyl)-phenylamino]-1-phenyl-methylidene}-5-cyclopropylsulphonylamino-2-indolinone,(Z)-3-{1-[4-(pyrrolidin-1-ylmethyl)-phenylamino]-1-phenyl-methylidene}-5-propylsulphonylamino-2-indolinone,(Z)-3-{1-[4-(pyrrolidin-1-ylmethyl)-phenylamino]-1-phenyl-methylidene}-5-ethylsulphonylamino-2-indolinone,(Z)-3-{1-[4-(pyrrolidin-1-ylmethyl)-phenylamino]-1-phenyl-methylidene}-5-methylsulphonylamino-2-indolinone,(Z)-3-{1-[4-(benzylaminocarbonyl)-phenylamino]-1-phenyl-methylidene}-5-phenylsulphonylamino-2-indolinone,(Z)-3-{1-[4-(N-dimethylaminocarbonylmethyl-N-acetyl-amino)-phenylamino]-1-phenyl-methylidene}-5-phenylsulphonylamino-2-indolinone,(Z)-3-[1-(4-piperidinomethyl-phenylamino)-1-phenyl-methylidene]-5-(4-aminophenylsulphonylamino)-2-indolinone,and(Z)-3-{1-[4-(N-(2-dimethylamino-ethyl)-N-methylsulphonyl-amino)-phenylamino)-1-phenyl-methylidene}-5-(N-methyl-N-phenylsulphonyl-amino)-2-indolinone,or a pharmaceutically acceptable salt thereof.
 13. A pharmaceuticalpreparation comprising a compound according to claim 1, 2, 3, 4, 5, 6,7, 8, 9, 10, 11 or 12 and a pharmaceutically acceptable carrier.
 14. Amethod for treating a disease characterised by excessive or abnormalcell proliferation which comprises administering a therapeutic amount ofa compound according to claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12.